CARMIL2 Deficiency

Mendelian MONDO:0029134 Pathograph 91 Show in embeddings browser Combined immunodeficiency Inborn error of immunity Primary immunodeficiency

CARMIL2 deficiency is an autosomal recessive combined immunodeficiency caused by biallelic loss-of-function variants in CARMIL2 (formerly RLTPR). Defective CARMIL2-dependent signaling impairs CD28 costimulation, T cell activation and immune memory; additional B cell and natural killer cell abnormalities broaden the phenotype beyond isolated CD28 deficiency. Recurrent respiratory and mucocutaneous infections, dermatitis, intestinal inflammation, growth failure and EBV-positive smooth muscle tumors occur with variable severity. Symptoms usually begin in infancy, but later onset occurs. Allogeneic hematopoietic cell transplantation can restore immunity and improve inflammatory disease and some tumors, with substantial transplant risks.

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Classifications

Harrison's Part

IUIS Category

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Mappings

MONDO

MONDO:0029134 severe combined immunodeficiency due to CARMIL2 deficiency

The exact MONDO concept includes CARMIL2 deficiency and immunodeficiency 58. The entry follows the clinical literature in using CARMIL2 deficiency; the canonical MONDO label is retained in the binding and synonyms.

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Inheritance

Autosomal recessive inheritance HP:0000007

Biallelic loss-of-function variants cause disease, usually in homozygous individuals but also in compound heterozygotes. In the 89-person ascertained cohort, the Results section reported 95% penetrance by age 10 and symptom onset from birth to age 22; this qualifies the abstract statement of full penetrance by age 10. Somatic reversion can modify severity.

Autosomal recessive inheritance Expressivity: VARIABLE

Show evidence (4 references)

PMID:28112205 SUPPORT PRIMARY RESULT Human Clinical

"Human CARMIL2-deficiency is therefore an autosomal recessive primary immunodeficiency disorder associated with defective CD28-mediated TCR co-signalling and impaired cytoskeletal dynamics."

States the autosomal recessive mode of inheritance directly.

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Penetrance reached 95% at 10 yr of age (Fig. 7 A)."

The detailed Results give age-dependent cohort penetrance, rather than establishing complete population penetrance.

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Median age at symptom onset was 1 yr (range: 0–22 yr; mean: 2.8 yr)."

Symptom onset extended into adulthood.

+ 1 more reference

Discussions and Knowledge Gaps

Which of CARMIL2's non-CD28 functions accounts for the parts of the phenotype that CD28 deficiency does not have - the low NK cell counts, the low memory B cells, the weak antibody responses, and the EBV-positive smooth muscle tumours?

KNOWLEDGE GAP OPEN gap_carmil2_beyond_cd28

Attached to

pathophysiology#B Cell Receptor-Proximal NF-kB Signaling Failure pathophysiology#Impaired Specific Antibody Production pathophysiology#Uncontrolled EBV Infection of Smooth Muscle phenotypes#Reduced Natural Killer Cell Count phenotypes#Decreased Memory B Cell Proportion

Patient B-cell assays establish a selective BCR-to-NF-kB defect. NK degranulation can also be impaired, and 2025 mouse genetics implicates CARMIL2/CD28 signaling in NK homeostasis. However, normal NK counts in human CD28 deficiency, variable NK lymphopenia in CARMIL2 deficiency, and the absence of direct EBV-smooth-muscle tumor killing assays leave the human tumor-surveillance mechanism unresolved.

Proposed experiments

Cell-intrinsic requirement for CARMIL2 in NK cells

exp_carmil2_nk_cell_intrinsic_requirement

Determine whether the NK cell deficit is NK-cell-intrinsic by testing CARMIL2-dependent receptor signalling in patient NK cells directly, and by comparing NK reconstitution kinetics after transplantation with those of the T cell compartment.

Which protein kinase C-coupled receptors need CARMIL2

exp_carmil2_pkc_receptor_panel

Test NF-kB activation in patient T, B and NK cells across a panel of receptors that signal through protein kinase C to CARD11, to establish whether CARMIL2 is a general requirement for that route or is specific to a subset of receptors.

Show evidence (2 references)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak."

Human phenotypes extend beyond isolated CD28 deficiency.

PMID:40402149 SUPPORT PRIMARY RESULT Model Organism

"The spleen of Cd28−/− and Carmil2−/− mice contained 1.5-fold reduced numbers of the NK cell as compared to the WT spleen, whereas the Carmil2QECd28−/− spleen expressed normal NK cell numbers (Fig. 4 G)."

Mouse genetics provides a partial mechanism for NK-cell homeostasis.

Do CARMIL2-deficient human T cells actually have a migration defect, and does any such defect contribute to disease?

KNOWLEDGE GAP OPEN gap_carmil2_cytoskeletal_defect_contested

Attached to

pathophysiology#Perturbed T Cell Cytoskeletal Organization

The earlier study measured cytoskeletal organization, speed, directionality and chemotaxis, whereas the later high-density collagen assay reported normal morphology. These are different readouts under different matrix conditions. The evidence supports context dependence rather than a universal contradiction; clinical consequences remain unproven.

Proposed experiments

Head-to-head migration assays in CARMIL2-deficient T cells

exp_carmil2_migration_assay_reconciliation

Run the assays behind both results side by side on the same patient cells - interstitial and transendothelial migration, polarity and uropod formation, and the three-dimensional collagen assay - reporting velocity and directionality as well as morphology, to establish whether the discrepancy is assay-dependent or patient-dependent.

Show evidence (1 reference)

PMID:34287962 SUPPORT PRIMARY RESULT In Vitro

"CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix."

Patient T cells retained normal morphology in high-density collagen.

Can bypassing the broken co-stimulatory signal downstream - with interleukin-2 or with glutamine - do anything useful for patients who cannot be transplanted?

KNOWLEDGE GAP OPEN gap_carmil2_metabolic_rescue_translation

Attached to

pathophysiology#Reduced Stimulated T Cell Proliferation pathophysiology#Reduced Activated T Cell mTOR Signaling treatments#Interleukin-2 Supplementation treatments#Glutamine Supplementation

IL-2 and glutamine improve selected patient-cell readouts in culture, but response depends on baseline impairment, stimulus and endpoint. Glutamine increased signaling and IL17A RNA without a significant secreted IL-17 increase, and proliferation improved in only two of four assayed patients. Neither intervention has established clinical efficacy or safety in CARMIL2 deficiency. Controlled studies would need endpoints beyond acute signaling rescue.

Proposed experiments

Compare the two ex vivo rescues on common readouts

exp_carmil2_bypass_agent_comparison

Test interleukin-2 and glutamine supplementation, alone and together, on the same panel of patient cells with common readouts - NF-kB and mTOR activity, proliferation, Th1 and Th17 cytokine output - to establish whether they act on the same bottleneck and whether either restores the Th17 arm that the mucosal fungal phenotype depends on.

Show evidence (4 references)

PMID:32201938 SUPPORT PRIMARY RESULT In Vitro

"In conclusion, we found that IL-2 rescued T cell activation and proliferation in CARMIL2-deficient patients."

The primary authors propose further study of IL-2.

PMID:40738287 SUPPORT PRIMARY RESULT In Vitro

"Glutamine supplementation restored NF-κB and mTOR activity, as measured by p-65 and RPS6 phosphorylation, respectively, and upregulated the expression of IL17A in CARMIL2-mutated CD4+ T cells."

The glutamine study reports cellular signaling rescue.

url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf SUPPORT PRIMARY RESULT In Vitro

"Glutamine supplementation improv ed proliferation only in T cells in which proliferati ve ca - pacity was completely abolished before the treatment (patients 1 and 4) ( Fig 4 , H )."

Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. Proliferation rescue was confined to two severely impaired patient cultures.

+ 1 more reference

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Pathophysiology

CARMIL2 Coding Substitutions

Mechanism confidence: Established

Biallelic coding substitutions include missense alleles and premature termination variants. Their effects must be interpreted using the relevant transcript and cellular assay.

CARMIL2 hgnc:27089

Genetic context CARMIL2 hgnc:27089 Variant type: single nucleotide variant Genomic context: coding sequence

Downstream

Reduced Functional CARMIL2 Protein The physical alteration compromises the encoded gene product through the documented molecular consequence.

Show evidence (2 references)

PMID:27647349 SUPPORT PRIMARY RESULT Human Clinical

"A1, A2, and A3 carry a homozygous nucleotide substitution (T>G) at position 1,115 in exon 14 of RLTPR, resulting in the replacement of a highly conserved leucine residue by an arginine (L372R) in the leucine-rich repeat (LRR) domain (Fig. 1, d and e; and Fig."

The founding kindred carried a homozygous coding missense substitution.

PMID:27647349 SUPPORT PRIMARY RESULT Human Clinical

"B1 and B2 carry a nucleotide substitution (C>T) at position 2,557 in exon 25, resulting in the replacement of a glutamine residue by a stop codon (Q853X; Fig. 1, d and e)."

A separate coding substitution introduces a premature stop.

CARMIL2 Coding Deletions

Mechanism confidence: Established

Coding deletions can alter the reading frame or remove amino acids in frame; a reported 13-base deletion reduced RNA and detectable protein.

CARMIL2 hgnc:27089

Genetic context CARMIL2 hgnc:27089 Variant type: deletion Genomic context: coding sequence

Downstream

Reduced Functional CARMIL2 Protein The physical alteration compromises the encoded gene product through the documented molecular consequence.

Show evidence (1 reference)

PMID:29479355 SUPPORT PRIMARY RESULT Human Clinical

"After subjecting the exome capture data to all filters only one variant remained, a homozygous 13bp frameshift deletion in CARMIL2 predicted to cause premature truncation of the protein shortly downstream of its midpoint (NM_001013838.1:c.2536_2548del:p.L846Sfs*36) (Figure 1E)."

Coding deletions can alter the reading frame or remove amino acids in frame; a reported 13-base deletion reduced RNA and detectable protein.

CARMIL2 Coding Insertions

Mechanism confidence: Established

A homozygous single-base insertion c.489insG was reported in affected patients and predicts premature termination; this is physically an insertion.

CARMIL2 hgnc:27089

Genetic context CARMIL2 hgnc:27089 Variant type: insertion Genomic context: coding sequence

Downstream

Reduced Functional CARMIL2 Protein The physical alteration compromises the encoded gene product through the documented molecular consequence.

Show evidence (1 reference)

PMID:28112205 SUPPORT PRIMARY RESULT Human Clinical

"The c.489insG and c.871+1G>T CARMIL2 mutations were confirmed by Sanger sequencing (see Supplemantary Table 5 for primer information)."

A homozygous single-base insertion c.489insG was reported in affected patients and predicts premature termination; this is physically an insertion.

CARMIL2 Intronic Splice Substitutions

Mechanism confidence: Established

Intronic substitutions disrupt splicing. A variant formerly annotated p.Arg385Thr in isoform 1 is intronic c.1149+5G>C in the predominant functional isoform 3.

CARMIL2 hgnc:27089

Genetic context CARMIL2 hgnc:27089 Variant type: single nucleotide variant Genomic context: intron

Downstream

Abnormal CARMIL2 RNA Processing The physical alteration compromises the encoded gene product through the documented molecular consequence.

Show evidence (2 references)

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"This G>C substitution was predicted to affect the splicing of transcripts 2 and 3 at position c.1149 + 5 (Fig. 1 I)."

Transcript-aware annotation identifies the intronic splice alteration.

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"Transcript 3 was expressed in HD cells, but RT-PCR and Sanger sequencing identified only transcript 1 in P42 T cell blasts, with the retention of 108 nucleotides of intron 14 (Fig. 1 K)."

Patient RNA confirms retention of the affected intron segment.

CARMIL2 Exonic Splice Substitutions

Mechanism confidence: Established

Exonic substitutions, including synonymous alleles, can create abnormal splice donors; a synonymous annotation does not imply normal RNA processing.

CARMIL2 hgnc:27089

Genetic context CARMIL2 hgnc:27089 Variant type: single nucleotide variant Genomic context: coding sequence

Downstream

Abnormal CARMIL2 RNA Processing The physical alteration compromises the encoded gene product through the documented molecular consequence.

Show evidence (2 references)

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"One missense (c.871G>C, p.Gly291Arg) and two synonymous (c.1128C>T and c.1578C>T) variants were also predicted to affect mRNA splicing."

Exonic missense and synonymous substitutions affect splicing.

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"CARMIL2 mRNA levels were also very low in T cell blasts from individuals with the c.1812-7G>A (P31), and c.1578C>T (P1) alleles, consistent with nonsense-mediated mRNA decay (Fig."

Some splice-altered transcripts are reduced.

Abnormal CARMIL2 RNA Processing

Mechanism confidence: Established

Patient RNA and minigene studies demonstrate exon skipping, intron retention or cryptic donor use. Some resulting transcripts are reduced, consistent with nonsense-mediated decay; decay is allele-specific and is not established for every premature stop.

CARMIL2 hgnc:27089

Downstream

Reduced Functional CARMIL2 Protein Abnormal transcripts can encode unstable or truncated products, or reduce protein dosage.

Show evidence (2 references)

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"Transcript 3 was expressed in HD cells, but RT-PCR and Sanger sequencing identified only transcript 1 in P42 T cell blasts, with the retention of 108 nucleotides of intron 14 (Fig. 1 K)."

RNA assays resolve the intronic effect of the transcript-dependent c.1149+5G>C allele.

PMID:29479355 SUPPORT PRIMARY RESULT In Vitro

"To check this we performed real-time RT-PCR on patient lymphoblastoid RNA and observed a highly significant drop of >75% in CARMIL2 expression levels for the F1 proband versus healthy controls (p < 0.0001)."

Reduced mutant RNA supports degradation for this frameshift allele; direct NMD inhibition was not tested.

Reduced Functional CARMIL2 Protein

Mechanism confidence: Established

Patient cells generally contain markedly reduced or absent functional CARMIL2. Missense stability differs between overexpression systems and lymphocytes. The Q853X transcript was not substantially degraded, and the available C-terminal antibody could not establish endogenous truncated-protein abundance; complete absence is therefore not universal.

CARMIL2 hgnc:27089

Downstream

Loss of CARMIL2 Scaffolding of CD28 to CARD11 Loss of functional CARMIL2 impairs assembly of the CD28-associated signaling scaffold.

B Cell Receptor-Proximal NF-kB Signaling Failure A second, CD28-independent consequence of the same lesion: patient B cells fail to activate NF-kB on B cell receptor stimulation, so the humoral defect is not solely downstream of the T cell defect.

Perturbed T Cell Cytoskeletal Organization Patient-cell assays link deficiency to context-dependent cytoskeletal organization and directional migration defects.

Reduced Natural Killer Cell Count NK lymphopenia is variable. Mouse genetic experiments implicate CARMIL2/CD28 signaling in NK homeostasis, but the human cellular route remains unresolved.

Reduced Natural Killer Cell Degranulation Patient-cell studies associate functional CARMIL2 loss with this readout; the intervening molecular route is incompletely resolved.

Reduced Activated T Cell ASCT2 Abundance Patient-cell studies associate functional CARMIL2 loss with this readout; the intervening molecular route is incompletely resolved.

Impaired Activation-Induced T Cell Metabolic Reprogramming Patient-cell studies associate functional CARMIL2 loss with this readout; the intervening molecular route is incompletely resolved.

Reduced Activated T Cell mTOR Signaling Patient-cell studies associate functional CARMIL2 loss with this readout; the intervening molecular route is incompletely resolved.

Show evidence (5 references)

PMID:29479355 SUPPORT PRIMARY RESULT In Vitro

"Similarly there was a loss of detectable CARMIL2 for the F3 patients, indicating that the p.R50T missense mutation was leading to gross instability of the protein."

Patient lymphoblastoid cells carrying p.R50T lacked detectable protein.

PMID:29479355 SUPPORT PRIMARY RESULT In Vitro

"It is worth noting, however, that the CARMIL2 band intensity varied considerably between our normal controls, and therefore residual protein expression (as well as weak expression of a truncated form) in our patients cannot be ruled out."

The primary authors acknowledge antibody/sensitivity limitations.

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"All the cells tested contained very little CARMIL2 protein, if any."

Patient-cell testing across the available alleles demonstrated low or absent protein.

+ 2 more references

Loss of CARMIL2 Scaffolding of CD28 to CARD11

Mechanism confidence: Established

CARMIL2 couples CD28-associated signaling to CARD11/CARMA1. Its scaffolding role is separable from capping-protein binding: experimentally disrupting the CPI motif preserves CD28 costimulation in mice.

CD28-to-CARD11 scaffolding activity GO:0030674 ⇓ LOSS OF FUNCTION

Animal models

Rltpr bas L432P Mouse Mouse recapitulates The mutant protein reaches the synapse with CD28 but fails to connect it to protein kinase C-theta and Carma1, which is precisely the scaffolding failure this node describes.

Rltpr CPI-Motif Mutant Mouse Mouse fails to recapitulate Disruption of the CPI motif does not abolish CD28 costimulation or Treg development.

Carmil2QE gain-of-function knock-in mouse Mouse perturbs A gain-of-function perturbation of the same node the disease loses. It does not model the disease state; it tests, in the opposite direction, whether the CARMIL2-CARD11 complex is the operative element of CD28 co-stimulation.

Downstream

Failure of CD28-Dependent Canonical NF-kB Activation With the bridge gone, CD28 engagement no longer reaches NF-kB.

Show evidence (3 references)

PMID:27647348 SUPPORT PRIMARY RESULT In Vitro

"Here, using affinity purification followed by mass spectrometry analysis, we showed that RLTPR acts as a scaffold, bridging CD28 to the CARD11/CARMA1 cytosolic adaptor and to the NF-κB signaling pathway, and identified proteins not found before within the CD28 signaling pathway."

Identifies the scaffolding function this node stands for, and the two partners it bridges.

PMID:27647348 SUPPORT PRIMARY RESULT In Vitro

"Although RLTPR is thought to function as an actin-uncapping protein, this property was dispensable for CD28 co-stimulation in both mouse and human."

The reason the pathograph routes co-stimulation failure through scaffolding rather than through the actin-uncapping activity, and the reason the cytoskeletal node is kept off this chain.

PMID:23793062 SUPPORT PRIMARY RESULT Model Organism

"However, the connection between CD28 and protein kinase C-θ and Carma1, two key effectors of CD28 costimulation, was abrogated in T cells expressing mutant Rltpr, and CD28 costimulation did not occur in those cells."

The mouse experiment that established the broken connection, at the level of the specific effectors. Human confirmation is carried by the two preceding items.

Failure of CD28-Dependent Canonical NF-kB Activation

Mechanism confidence: Established

CD28 costimulation fails to enhance canonical NF-kB activation appropriately. TCR-proximal signaling and several AP-1/NFAT outputs are retained. Impaired PMA-induced NF-kB activation in primary patient T cells also demonstrates a CARMIL2 requirement beyond engagement of CD28 itself.

T cell CL:0000084

T cell costimulation GO:0031295 ⇓ LOSS OF FUNCTION CD28-dependent canonical NF-kB activation GO:0043123 ↓ DECREASED

Experimental models

Patient T Cell Costimulation and Isoform Complementation PRIMARY CELL CULTURE Isoform 3 restored NF-kB activation after both stimuli.

CARMIL2-Deficient Jurkat Variant Assays CELL LINE Patient alleles impaired CD28 signaling in complementation assays.

Downstream

Regulatory T Cell Deficit The observed immune defect can contribute to this consequence, but the complete cellular and tissue route is not established.

Memory T Cell Deficit The observed immune defect can contribute to this consequence, but the complete cellular and tissue route is not established.

Impaired Specific Antibody Production Antibody responses are T-cell-dependent, so loss of CD4+ helper output is one route to the humoral defect. It is not the only one - see the B cell receptor node.

Impaired CD3/CD28-Induced T Cell Proliferation The unresponsiveness of patient CD4+ T cells to CD28 stimulation is the direct functional readout of this signalling failure.

Reduced T Cell Interleukin-2 Production Impaired costimulation reduces induction of IL-2.

Altered Activated T Cell Survival Program Deficient costimulation is associated with this altered T-cell program.

Impaired T Follicular Helper Cell Support Deficient costimulation is associated with this altered T-cell program.

Reduced CD25 Induction Costimulation-dependent activation fails to induce normal CD25 expression.

Show evidence (4 references)

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28."

Establishes both halves of this node across the whole allelic series: the canonical NF-kB arm fails, and the AP-1 and NFAT arms do not.

PMID:27647349 SUPPORT PRIMARY RESULT In Vitro

"Their CD4+ T cells do not respond to CD28 stimulation."

The functional readout in patient cells.

PMID:29479355 SUPPORT PRIMARY RESULT In Vitro

"CD3/CD28 signaling impairment was evidenced by reduced proliferative response to stimulation."

Independent replication of the co-stimulation defect as a proliferation readout in a separate cohort.

+ 1 more reference

Regulatory T Cell Deficit

Mechanism confidence: Established

Circulating regulatory T cell numbers are substantially reduced, with low CD25 and CTLA4 expression in studied cohorts. Impaired generation and maintenance contribute to loss of immune regulation; residual Tregs are not universally absent.

FOXP3+ regulatory T cell CL:0000815

regulatory T cell differentiation GO:0045066 ↓ DECREASED

Animal models

Rltpr bas L432P Mouse Mouse recapitulates The model has reduced Treg development; residual Tregs are present.

Rltpr Null Mouse Mouse partially recapitulates Regulatory-cell abundance is reduced.

Carmil2QE gain-of-function knock-in mouse Mouse rescues The gain-of-function allele restores regulatory-cell numbers in Cd28-null mice.

Downstream

Mucocutaneous and Intestinal Immune Dysregulation Loss of regulatory T cells is the standing explanation for the dermatitis and inflammatory bowel disease, but the intermediate steps between the Treg deficit and the specific tissue inflammation have not been dissected in this disease.

Decreased Regulatory T Cell Proportion The measured fall in circulating CD4+ regulatory T cells is the direct laboratory expression of this deficit.

Show evidence (4 references)

PMID:28112205 SUPPORT PRIMARY RESULT Human Clinical

"These patients lack regulatory T cells without evidence of organ-specific autoimmunity, and have defective CD28 co-signalling associated with impaired T-cell activation, differentiation and function, as well as perturbed cytoskeletal organization associated with T-cell polarity and migration disorders."

Establishes the Treg deficit and, importantly, its dissociation from organ-specific autoimmunity.

PMID:32625199 SUPPORT PRIMARY RESULT Human Clinical

"FOXP3+ regulatory T cells (Treg) were also quantitatively decreased, and furthermore CD25 expression within the Treg subset was substantially reduced."

Adds the qualitative defect within the surviving Treg compartment to the quantitative one.

PMID:23793062 SUPPORT PRIMARY RESULT Model Organism

"We found that Rltpr was a lymphoid cell-specific, actin-uncapping protein essential for costimulation via CD28 and the development of regulatory T cells."

The mouse genetics that predicted the human Treg deficit; kept distinct from the two human observations above by `evidence_source`.

+ 1 more reference

Memory T Cell Deficit

Mechanism confidence: Established

Reduced CD4+ and CD8+ memory T cell compartments accompany impaired costimulation. Both deficient expansion and maintenance are plausible contributors; total T cell numbers may remain normal.

memory T cell CL:0000813

memory T cell differentiation GO:0043379 ↓ DECREASED

Downstream

Failure of Cell-Mediated Control of Chronic Viral and Fungal Infection The observed immune defect can contribute to this consequence, but the complete cellular and tissue route is not established.

Decreased Memory T Cell Proportion The measured fall in CD4+ and CD8+ memory T cell counts is the direct laboratory expression of this deficit.

Show evidence (2 references)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs."

Quantifies the memory T cell deficit and, in the same sentence, marks it as one of the features shared with CD28 deficiency.

PMID:29479355 SUPPORT PRIMARY RESULT Human Clinical

"Immunophenotyping revealed that patient Treg counts were significantly depressed, and that CD4+ T cells were heavily skewed towards the naïve status."

The naive skew is the mirror image of the memory deficit, measured in an independent cohort.

Failure of Cell-Mediated Control of Chronic Viral and Fungal Infection

Mechanism confidence: Established

Deficient T-cell activation, memory and effector output, together with variable NK dysfunction, compromise antimicrobial control. The contributions of individual immune abnormalities vary by pathogen and are not fully resolved.

T cell mediated immunity GO:0002456 ↓ DECREASED

Animal models

Naturally Occurring Canine CARMIL2 R291Ter Dog partially recapitulates The naturally occurring canine disorder partially parallels human susceptibility to infection.

Downstream

Uncontrolled Cutaneous Papillomavirus and Poxvirus Replication The observed immune defect can contribute to this consequence, but the complete cellular and tissue route is not established.

Uncontrolled EBV Infection of Smooth Muscle The observed immune defect can contribute to this consequence, but the complete cellular and tissue route is not established.

Recurrent Mucocutaneous Candidiasis The observed immune defect can contribute to this consequence, but the complete cellular and tissue route is not established.

Recurrent Infections The general infection burden is the direct clinical expression of this node.

Recurrent Upper Respiratory Tract Infections Combined immune dysfunction increases susceptibility; the individual contribution of each immune compartment varies.

Recurrent Lower Respiratory Tract Infections Combined immune dysfunction increases susceptibility; the individual contribution of each immune compartment varies.

Bacterial Skin Abscesses Combined immune dysfunction increases susceptibility; the individual contribution of each immune compartment varies.

Severe Cytomegalovirus Infection Combined immune dysfunction increases susceptibility; the individual contribution of each immune compartment varies.

Bronchiectasis Repeated respiratory infection can lead to chronic airway injury.

Show evidence (2 references)

PMID:27647349 SUPPORT PRIMARY RESULT Human Clinical

"The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis."

Sets out the breadth of the infection burden, including the mycobacterial and mucosal-fungal infections that mark a Th1/Th17 defect.

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease."

The cohort-scale statement of the infection burden, alongside the two other defining manifestations.

Uncontrolled Cutaneous Papillomavirus and Poxvirus Replication

Mechanism confidence: Established

Impaired cutaneous viral control permits HPV warts and molluscum contagiosum. Lesions can persist or become widespread, but some are self-limited and onset varies.

keratinocyte CL:0000312

Downstream

Recalcitrant Cutaneous Warts Papillomavirus outcome of the failed cutaneous control.

Persistent Molluscum Contagiosum Poxvirus outcome of the same failure.

Show evidence (2 references)

PMID:27896283 SUPPORT PRIMARY RESULT Human Clinical

"Four patients from three Norwegian families presented with a common skin phenotype of warts, molluscum contagiosum, and dermatitis since early childhood, and various other immunological features."

Documents both cutaneous viral outcomes together, and their onset in early childhood.

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs."

Confirms recalcitrant warts at cohort scale and identifies them as the feature shared with CD28 deficiency.

Uncontrolled EBV Infection of Smooth Muscle

Mechanism confidence: Established

EBV-positive smooth-muscle tumors arise in the setting of impaired immune surveillance. Deficient EBV-responsive T-cell expansion is demonstrable, but the precise link between individual immune defects and smooth-muscle infection or tumor growth remains unresolved.

smooth muscle cell CL:0000192

Experimental models

Autologous EBV Lymphoblastoid Cell and Patient T Cell Coculture CO CULTURE Patient T cells expanded poorly and lacked IFN-gamma secretion to autologous EBV-positive lymphoblastoid cells.

Downstream

EBV-Positive Smooth Muscle Tumor The tumour is the clinical expression of this node.

Show evidence (2 references)

PMID:28112205 SUPPORT PRIMARY RESULT Human Clinical

"Here, we show four human patients with EBV+ disseminated smooth muscle tumours that carry two homozygous loss-of-function mutations in the CARMIL2 (RLTPR) gene encoding the capping protein regulator and myosin 1 linker 2."

The tumours were the presenting feature in the original four patients, which is why they anchor this node.

PMID:32625199 SUPPORT PRIMARY RESULT Human Clinical

"CARMIL2 deficiency is a rare combined immunodeficiency (CID) characterized by defective CD28-mediated T cell co-stimulation, altered cytoskeletal dynamics, and susceptibility to Epstein Barr Virus smooth muscle tumors (EBV-SMTs)."

States the susceptibility as a defining feature of the disease rather than a single-family observation.

B Cell Receptor-Proximal NF-kB Signaling Failure

Mechanism confidence: Established

Anti-IgM stimulation of patient B cells fails to induce normal p65 phosphorylation and IκBα degradation. ERK signaling is relatively preserved, and CD40- and PMA-induced NF-kB responses remain intact in the reported assays. Mouse B cells do not reproduce this selective human defect.

B cell CL:0000236

B cell receptor signaling pathway GO:0050853 ↓ DECREASED

Experimental models

Patient B Cell Receptor Stimulation PRIMARY CELL CULTURE Anti-IgM-induced NF-kB activation is impaired while CD40 responses remain intact.

Animal models

Rltpr bas L432P Mouse Mouse fails to recapitulate Mouse B-cell proliferative responses and T-independent antibody responses were preserved.

Downstream

Impaired Specific Antibody Production The observed immune defect can contribute to this consequence, but the complete cellular and tissue route is not established.

Reduced Memory B Cell Compartment Disrupted signaling and T-cell help are plausible contributors to formation or maintenance of B-cell memory.

Show evidence (3 references)

PMID:27647349 SUPPORT PRIMARY RESULT In Vitro

"This B cell phenotype does not result solely from the T cell deficiency, as the patients' B cells fail to activate NF-κB upon B cell receptor (BCR) stimulation."

Both the measurement and the inference this node exists to record: the humoral defect has its own proximal cause.

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Our study suggests that CARMIL2 governs immunological pathways beyond CD28."

The cohort study's own conclusion, which is the general form of the claim this node instantiates.

PMID:27647349 SUPPORT PRIMARY RESULT In Vitro

"These data show that RLTPR-deficient B cells have a partially defective signaling pathway, at least via NF-κB, but an intact CD40 signaling pathway, at least for the readouts tested."

The defect is pathway-specific rather than a failure of every B-cell stimulus.

Impaired Specific Antibody Production

Mechanism confidence: Established

Specific antibody responses, especially to protein vaccines, are weak despite frequently normal total serum IgG. Both B-cell-intrinsic signaling and deficient T-cell help contribute.

memory B cell CL:0000787

Downstream

Impaired Specific Antibody Response The measurable clinical expression of this node.

Reduced IgG The humoral defect is variably expressed in serum and memory-cell readouts.

Show evidence (3 references)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak."

Establishes the humoral deficit and marks it as one of the features that separates CARMIL2 from CD28 deficiency.

PMID:27647349 SUPPORT PRIMARY RESULT Human Clinical

"The patients also display few memory B cells and poor antibody responses."

The original description of the same deficit.

PMID:32625199 SUPPORT PRIMARY RESULT Human Clinical

"Defects in both T and B cell compartments were observed, including absent central memory CD8+ T cells, and decreased frequencies of total and class-switched memory B cells."

Adds the class-switched memory B cell subset to the general memory B cell deficit.

Perturbed T Cell Cytoskeletal Organization

Mechanism confidence: Established

Patient T-cell assays showed disorganized microtubules and leading-edge actin, increased spontaneous velocity but reduced directional migration and CXCL12 chemotaxis. Total F-actin and CXCR4 were preserved. A later, denser collagen assay found normal cellular morphology; it did not measure or refute every earlier migration endpoint. The contribution to clinical disease remains uncertain.

T cell CL:0000084

actin cytoskeleton organization GO:0030036 ⚠ ABNORMAL

Experimental models

Patient T Cell Cytoskeleton and Migration Assays PRIMARY CELL CULTURE Patient-cell assays support a directional migration defect despite increased spontaneous speed.

Patient T Cells in Dense Three-Dimensional Collagen PRIMARY CELL CULTURE Cells had normal morphology in this assay.

Show evidence (2 references)

PMID:28112205 SUPPORT PRIMARY RESULT In Vitro

"Our studies in CARMIL2-deficient T lymphoblasts showed impaired actin distribution in the leading edge and a severely disturbed microtubule network associated with increased spontaneous migratory speed but decreased directness and chemokine-directed migration."

Direct patient-cell assays document multiple cytoskeletal and migration endpoints.

PMID:34287962 SUPPORT PRIMARY RESULT In Vitro

"CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix."

Normal morphology in high-density collagen limits generalization.

Mucocutaneous and Intestinal Immune Dysregulation

Mechanism confidence: Established

Reduced regulatory-cell activity and broader immune dysfunction contribute to inflammatory skin and intestinal disease. Clinical improvement after immune reconstitution supports an immune contribution. Epithelial-intrinsic effects and the tissue mechanism of gastrointestinal stenosis remain unresolved; fibrosis has not been demonstrated.

Downstream

Atopic Dermatitis The cutaneous expression of this node.

Inflammatory Bowel Disease The intestinal expression of this node.

Failure to Thrive Intestinal inflammation and chronic diarrhea contribute to poor growth through nutritional and inflammatory burdens.

Chronic Diarrhea Chronic diarrhoea is the symptomatic expression of the intestinal inflammation, and is the intermediate this node's failure-to-thrive edge already names.

Psoriasiform Dermatitis Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.

Seborrheic Dermatitis Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.

Eosinophilic Enteropathy Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.

Esophageal Stenosis Chronic inflammation is a proposed contributor; tissue fibrosis and the specific mechanism of narrowing have not been demonstrated.

Pyloric Stenosis Chronic inflammation is a proposed contributor; tissue fibrosis and the specific mechanism of narrowing have not been demonstrated.

Duodenal Stenosis Chronic inflammation is a proposed contributor; tissue fibrosis and the specific mechanism of narrowing have not been demonstrated.

Food Allergy Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.

Asthma Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.

Rhinitis Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.

Eosinophilia Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.

Elevated IgE Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.

Membranous Nephropathy An immune-mediated contribution is proposed in a single case; causation and the relevant cellular route remain uncertain.

Autoimmune Hemolytic Anemia An immune-mediated contribution is proposed in a single case; causation and the relevant cellular route remain uncertain.

Show evidence (2 references)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease."

Names mucocutaneous inflammation and inflammatory bowel disease as defining manifestations at cohort scale.

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"IBD was the most severe clinical manifestation, leading to growth retardation, requiring multiple interventional treatments."

Establishes the clinical weight of the intestinal arm relative to the rest of the phenotype.

Reduced T Cell Interleukin-2 Production

Mechanism confidence: Established

CD28-dependent induction of IL-2 is impaired. This reduces a key growth signal, although cytokine output varies with stimulus and time point.

interleukin-2 production GO:0032623

Downstream

Reduced Stimulated T Cell Proliferation Deficient growth-factor output contributes to impaired proliferation; IL-2 rescue supports this route.

Show evidence (1 reference)

PMID:27647349 SUPPORT PRIMARY RESULT In Vitro

"In contrast, TNF and IL-2 productions were not enhanced by CD28 costimulation in patients’ memory CD4+ T cells, although all memory CD4+ T cell express CD28 (Fig."

CD28 failed to augment IL-2 production in patient memory CD4 T cells.

Reduced Stimulated T Cell Proliferation

Mechanism confidence: Established

Patient T-cell proliferation is reduced with CD3/CD28 costimulation. Additional IL-2 can restore proliferation in some assays, whereas CD25 induction may remain subnormal.

T cell proliferation GO:0042098

Experimental models

IL-2 Rescue of Patient T Cells PRIMARY CELL CULTURE Proliferation improves in responsive patient cultures.

Downstream

Impaired CD3/CD28-Induced T Cell Proliferation The culture proliferation assay is the measurable phenotype of this cellular defect.

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"The addition of IL-2 to PBMCs cultures incubated with anti-CD3/CD28 mAb resulted in levels of CD4+ and CD8+ T cell proliferation similar to those observed in HD cell cultures or sorted naive T cells (Fig."

Proliferation is a rescuable cellular readout, not proof of clinical treatment efficacy.

Altered Activated T Cell Survival Program

Mechanism confidence: Provisional

Activated patient CD4 T cells show reduced induction of prosurvival BCL2L1 and increased BCL2L11 in memory cells. Impaired survival is a proposed explanation for reduced cell accumulation; direct apoptosis quantification was not established by these transcript measurements.

Downstream

Reduced Th1 Effector Output Impaired persistence is a proposed contributor; transcript measurements do not establish the entire causal sequence.

Reduced Th17 Effector Output Impaired persistence is a proposed contributor; transcript measurements do not establish the entire causal sequence.

Memory T Cell Deficit Impaired persistence is a proposed contributor; transcript measurements do not establish the entire causal sequence.

Show evidence (1 reference)

PMID:27647349 SUPPORT PRIMARY RESULT In Vitro

"Whereas no significant difference of BCL2 expression was detected in both naive and memory RLTPR-deficient CD4+ T cells, we found significantly lower induction of BCL2L1 in RLTPR-deficient naive (fivefold reduced) and memory (twofold reduced) CD4+ T cells and increased (fourfold) expression of..."

The survival-program interpretation is based on expression of apoptosis regulators.

Reduced Th1 Effector Output

Mechanism confidence: Established

Accumulated IFN-gamma and other Th1 cytokine outputs are reduced in patient cultures. Preserved TBX21 induction and cytokine-positive fractions among viable cells argue against an absolute inability to specify the Th1 lineage.

Downstream

Failure of Cell-Mediated Control of Chronic Viral and Fungal Infection Reduced effector capacity plausibly contributes to susceptibility, with pathogen-specific contributions unresolved.

Show evidence (2 references)

PMID:27647349 SUPPORT PRIMARY RESULT In Vitro

"RLTPR-deficient memory CD4+ T cells exhibited dramatic reductions in production of IFN-γ, TNF, IL-17A/F, and IL-22 (Fig. 6 g), as well as IL-6 and IL-10 (Fig. 6 h)."

Reduced cytokine accumulation is the direct readout.

PMID:27647349 SUPPORT PRIMARY RESULT In Vitro

"Surprisingly, induction of TBX21 and RORC expression in RLTPR-deficient naive CD4+ T cells was comparable with that observed for control naive CD4+ T cells."

Lineage transcription-factor induction was preserved.

Reduced Th17 Effector Output

Mechanism confidence: Established

IL-17A/F and IL-22 output is reduced under several stimulation conditions. RORC induction and viable cytokine-positive fractions can be preserved, so survival and activation defects may underlie the output deficit. Later metabolic rescue increased IL17A RNA without a significant increase in secreted IL-17.

Downstream

Failure of Cell-Mediated Control of Chronic Viral and Fungal Infection Reduced effector capacity plausibly contributes to susceptibility, with pathogen-specific contributions unresolved.

Show evidence (1 reference)

PMID:27647349 SUPPORT PRIMARY RESULT In Vitro

"Consistent with this interpretation, analysis of the proportion of viable RLTPR-deficient CD4+ T cells expressing Th1 and Th17 cytokines, as determined by intracellular staining, was similar to controls (not depicted), suggesting the reduction in levels of accumulated secreted cytokines during..."

Viable-cell analysis argues for a survival contribution rather than a universal differentiation block.

Impaired T Follicular Helper Cell Support

Mechanism confidence: Established

Circulating Tfh cells are reduced, and activated naive patient T cells show reduced ICOS and CD40L expression. These findings support deficient T-cell help as one contributor to impaired humoral immunity.

Downstream

Impaired Specific Antibody Production Reduced T-cell help can compromise antigen-specific B-cell memory and antibody responses.

Reduced Memory B Cell Compartment Disrupted signaling and T-cell help are plausible contributors to formation or maintenance of B-cell memory.

Show evidence (2 references)

PMID:27647349 SUPPORT PRIMARY RESULT In Vitro

"Frequency of CD40L and MFI of ICOS on RLTPR-deficient naive CD4+ T cells were reduced, equating to ∼50% of the levels detected on cells from healthy controls."

ICOS and CD40L were approximately half of control levels.

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"All tested patients in our cohort had low Treg and cTFH cells, impaired proliferation in response to anti-CD28, and low production of IL-2, IL-17, and IL-21 cytokines after CD28 crosslinking."

Patient immunophenotyping identifies reduced circulating Tfh cells.

Reduced Natural Killer Cell Degranulation

Mechanism confidence: Established

Patient NK cells showed reduced K562-induced degranulation and NKG2D expression; IL-2 prestimulation abolished the measured differences. Functional impairment is distinct from variable NK lymphopenia.

natural killer cell degranulation GO:0043320

Experimental models

Patient NK Cell K562 Degranulation Assay CO CULTURE K562-induced degranulation and NKG2D expression were reduced.

Downstream

Failure of Cell-Mediated Control of Chronic Viral and Fungal Infection Reduced effector capacity plausibly contributes to susceptibility, with pathogen-specific contributions unresolved.

Show evidence (2 references)

PMID:28112205 SUPPORT PRIMARY RESULT In Vitro

"NK-cell degranulation in response to co-incubation with the erythroleukemic cell line K562 was impaired and accompanied by a decreased expression of NKG2D."

K562-induced NK degranulation was reduced.

PMID:28112205 SUPPORT PRIMARY RESULT In Vitro

"NK cell and CD8 T-cell pre-culturing with IL-2 abrogated the observed differences in degranulation and NKG2D expression (Fig. 6)."

The functional readouts improved after IL-2 pretreatment.

Reduced Activated T Cell ASCT2 Abundance

Mechanism confidence: Established

Activated patient CD4 T cells have reduced surface abundance of the glutamine transporter ASCT2. Transporter expression is measured; reduced glutamine uptake is inferred rather than directly quantified.

Downstream

Impaired Activation-Induced T Cell Metabolic Reprogramming Reduced transporter availability is a candidate contributor, but uptake and metabolic flux were not directly established.

Show evidence (1 reference)

url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf SUPPORT PRIMARY RESULT In Vitro

"Reduced expr ession of ASCT2, the major glutamine trans - porter in T cells, was further confirmed by flo w cytometry"

Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. Flow cytometry confirmed lower surface ASCT2 in activated patient T cells.

Impaired Activation-Induced T Cell Metabolic Reprogramming

Mechanism confidence: Established

Activated patient CD4 T cells show altered transcript and metabolite profiles involving glycolysis, amino-acid metabolism and related pathways. These measurements establish altered abundance, not direct pathway flux or systemic glutamine deficiency.

Experimental models

Patient CD4 T Cell Metabolic Profiling and Glutamine Rescue PRIMARY CELL CULTURE Patient cells show altered metabolic transcripts and metabolite abundance.

Downstream

Reduced Activated T Cell mTOR Signaling Metabolic supplementation rescues signaling, consistent with coupling; directionality and feedback remain incompletely resolved.

Show evidence (2 references)

PMID:40738287 SUPPORT PRIMARY RESULT In Vitro

"RNA sequencing of CD4+ T cells revealed decreased expression of genes associated with metabolic activity, including mTOR signaling, glycolysis, 1-carbon metabolism, and glutamine metabolism."

Activated patient CD4 T cells have altered metabolic transcript abundance.

PMID:40738287 SUPPORT PRIMARY RESULT In Vitro

"Whole-cell metabolomics reinforced these results and highlighted glutamine deficiency as a potential driver of the observed metabolic phenotype."

Metabolite abundance supports the phenotype without establishing flux.

Reduced Activated T Cell mTOR Signaling

Mechanism confidence: Established

Reduced phosphorylation of ribosomal protein S6 indicates impaired mTOR-pathway activation in stimulated patient CD4 T cells. Glutamine supplementation improved this readout in culture.

TORC1 signaling GO:0038202

Experimental models

Patient CD4 T Cell Metabolic Profiling and Glutamine Rescue PRIMARY CELL CULTURE Glutamine increased RPS6 phosphorylation.

Show evidence (1 reference)

PMID:40738287 SUPPORT PRIMARY RESULT In Vitro

"Glutamine supplementation restored NF-κB and mTOR activity, as measured by p-65 and RPS6 phosphorylation, respectively, and upregulated the expression of IL17A in CARMIL2-mutated CD4+ T cells."

RPS6 phosphorylation is the reported mTOR readout.

Reduced Memory B Cell Compartment

Mechanism confidence: Established

Circulating memory B cells, including class-switched cells, are reduced in many patients. The relative contributions of B-cell-intrinsic signaling and impaired T-cell help remain uncertain.

Downstream

Decreased Memory B Cell Proportion Low circulating memory B cell counts are the cellular counterpart of the impaired humoral memory, and one of the two features that separate CARMIL2 deficiency from CD28 deficiency.

Decreased Class-Switched Memory B Cells The humoral defect is variably expressed in serum and memory-cell readouts.

Show evidence (2 references)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"Similarly, B cell counts were low in only one patient (P2), but nine (60%) had low percentages of class-switched memory B cells concomitant with elevated naïve B cells."

The longitudinal cohort quantifies class-switched memory deficiency.

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak."

The larger cohort confirms the memory B-cell deficit.

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Pathograph

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Phenotypes

Blood 11

Decreased Regulatory T Cell Proportion HP:0020113

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs."

Reports the low Treg counts at cohort scale.

Decreased Memory T Cell Proportion HP:0032183

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs."

Reports the low memory T cell counts at cohort scale.

Decreased Memory B Cell Proportion HP:0030374

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak."

Reports the memory B cell deficit and marks it as discriminating against CD28 deficiency.

Reduced Natural Killer Cell Count Reduced total natural killer cell count HP:0040218

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak."

Reduced NK counts were frequent in later cohorts, including 13/15 in the longitudinal series, but normal counts were reported in the initial six-patient series; NK lymphopenia is not obligatory.

Impaired CD3/CD28-Induced T Cell Proliferation Decreased antigen-specific T cell proliferation HP:0031402

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"These results confirm that CARMIL2 deficiency results in markedly impaired CD28 cosignaling, leading to lower T cell proliferation capacities, as observed in individuals with CD28 deficiency (Béziat et al., 2021), and that these phenotypes can be rescued by the addition of IL-2, at least in vitro."

Reduced proliferation after CD3/CD28 stimulation is a characteristic functional finding even when total circulating T-cell counts are preserved. Responses depend on the stimulus and cell subset.

Eosinophilia FREQUENT Increased total eosinophil count HP:0001880

Show evidence (1 reference)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"During the time of evaluation, eosinophilia was detected in seven patients (47%)."

Peripheral eosinophilia was present in 7/15 (47%) at evaluation in the longitudinal cohort.

Elevated IgE OCCASIONAL Increased circulating IgE concentration HP:0003212

Show evidence (1 reference)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"IgE was slightly elevated in three (20%) patients."

IgE was elevated in 3/15 (20%) in the longitudinal cohort; normal or low concentrations also occur.

Reduced IgG OCCASIONAL Decreased circulating IgG concentration HP:0004315

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"We analyzed the impact of this defect on B cell function and found that serum IgG concentrations were within the normal range in most CARMIL2-deficient individuals, as only 12/80 (15%) presented hypogammaglobulinemia (Fig. 6 A and Table S4)."

Reduced serum IgG occurred in 12/80 (15%); normal IgG does not exclude functional antibody deficiency.

Decreased Class-Switched Memory B Cells FREQUENT Decreased class-switched memory B cell proportion HP:0030388

Show evidence (1 reference)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"Similarly, B cell counts were low in only one patient (P2), but nine (60%) had low percentages of class-switched memory B cells concomitant with elevated naïve B cells."

Class-switched memory B cells were low in 9/15 (60%) in the longitudinal cohort.

Reduced CD25 Induction Decreased CD25 upregulation upon TCR activation HP:0031270

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"CD25 upregulation following anti-CD3/CD28 stimulation of PBMCs was also increased by exogenous IL-2, however it did not reach the levels of healthy control cells (Fig."

CD25 induction after CD3/CD28 stimulation is reduced and may remain below control levels despite IL-2 supplementation.

Autoimmune Hemolytic Anemia HP:0001890

Show evidence (2 references)

PMID:39649299 SUPPORT PRIMARY RESULT Human Clinical

"Her laboratory results showed 24-hour urine protein level of 63 mg/m2/h, hypoalbuminemia (serum albumin: 2.9 g/dL (3.5–5 g/dL); severe anemia (hemoglobin 3.8 g/dL (11–15 g/dL)), elevated erythrocyte sedimentation rate (104 mm/h), and a positive directs Coombs test."

Coombs-positive hemolytic anemia was described in the same renal case; this rare association does not establish a common autoimmune phenotype.

PMID:39649299 SUPPORT PRIMARY RESULT Human Clinical

"We hypothesize that a reduced number of Treg cells can lead to the breakdown of immune tolerance leading to the secondary phenotype of membranous nephropathy and autoimmune hemolytic anemia."

The case authors identify autoimmune hemolytic anemia.

Digestive 6

Inflammatory Bowel Disease OCCASIONAL Colitis HP:0002583

Temporal: CHRONIC

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"GI manifestations were reported in 55/87 (63%) CARMIL2-deficient individuals, of whom 19/87 (22%) had histologically confirmed inflammatory bowel disease (IBD)."

Histologically confirmed inflammatory bowel disease occurred in 19/87 (22%); onset was often before age 6 but can be later. Severe colitis may resist medical treatment.

Chronic Diarrhea OCCASIONAL HP:0002028

Temporal: CHRONIC

Show evidence (1 reference)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%), recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%), and EBV-related leiomyoma (n = 2, 13%)."

Chronic diarrhoea in 4 of 15 patients (27 per cent) is the `OCCASIONAL` band.

Eosinophilic Enteropathy OCCASIONAL Gastrointestinal eosinophilia HP:0032064

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Eosinophilic enteropathy, usually manifesting as esophagitis, was observed in 21/87 individuals (24%)."

Eosinophilic enteropathy affected 21/87 (24%), often as esophagitis.

Esophageal Stenosis HP:0010450

Show evidence (1 reference)

url:https://all-imm.com/index.php/aei/article/view/1595/2445 SUPPORT PRIMARY RESULT Human Clinical

"At 16 years, he developed progressive dysphagia due to esophageal stricture with associated esophagitis and nodular pangastritis, partially relieved by pneumatic dilation."

Esophageal narrowing can cause progressive dysphagia and may require dilation; the tissue mechanism is unresolved.

Pyloric Stenosis HP:0002021

Show evidence (1 reference)

url:https://all-imm.com/index.php/aei/article/view/1595/2445 SUPPORT PRIMARY RESULT Human Clinical

"Pyloric stenosis occurred at 6 years and was surgically corrected, resulting in complete resolution."

Pyloric obstruction has required surgery in affected children, including two siblings with symptom resolution after repair.

Duodenal Stenosis HP:0100867

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"In nine individuals, upper GI tract involvement led to esophageal, pyloric, or duodenal stenosis."

Duodenal narrowing is a reported upper gastrointestinal complication. Aggregate stenosis counts are not assigned to each anatomical site.

Genitourinary 1

Membranous Nephropathy HP:0012578

Show evidence (1 reference)

PMID:39649299 SUPPORT PRIMARY RESULT Human Clinical

"Her renal biopsy was suggestive of membranous nephropathy."

A single child with biallelic CARMIL2 variation had biopsy-confirmed secondary membranous nephropathy and nephrotic syndrome. Its frequency and direct mechanistic relationship to CARMIL2 remain uncertain.

Head and Neck 2

Recurrent Upper Respiratory Tract Infections FREQUENT HP:0002788

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Recurrent upper and lower respiratory tract infections were noted in 53/87 (61%) and 53/87 (61%) CARMIL2-deficient individuals, respectively (Fig. 7 E)."

Recurrent upper respiratory infections occurred in 53/87 (61%).

Rhinitis OCCASIONAL HP:0012384

Show evidence (1 reference)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"P3, P7, and P15 (20% of patients) had rhinitis, with chronic nasal congestion and rhinorrhea, which was sensitive to intranasal corticosteroids."

Rhinitis with congestion and rhinorrhea occurred in 3/15 (20%) and responded to intranasal corticosteroids.

Immune 12

Persistent Molluscum Contagiosum OCCASIONAL Unusual molluscum contagiosum HP:0032163

Temporal: CHRONIC

Show evidence (1 reference)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"Another common viral skin infection was molluscum contagiosum (n=3, 20%, Table 1)."

Molluscum contagiosum occurred in 3/15 patients (20%) in a longitudinal cohort and can be persistent or extensive.

Recurrent Mucocutaneous Candidiasis OCCASIONAL Chronic mucocutaneous candidiasis HP:0002728

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Bacterial skin abscesses occurred in 26/87 (30%), and chronic mucocutaneous candidiasis, presenting as oral thrush, intertrigo, onychomycosis, and/or esophagitis, occurred in 24/87 (28%) CARMIL2-deficient individuals."

Chronic mucocutaneous candidiasis affected 24/87 (28%) in the large cohort, including oral, intertriginous, nail or esophageal disease.

Recurrent Infections FREQUENT HP:0002719

Temporal: RECURRENT

Show evidence (1 reference)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

Reports recurrent infections in 10 of 15 patients (67 per cent), which is the `FREQUENT` band.

Atopic Dermatitis FREQUENT HP:0001047

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Atopic dermatitis affected 60/87 (69%) CARMIL2-deficient individuals within the first 2 yr of life (Fig. 7 F)."

Atopic dermatitis occurred in 60/87 (69%) in the large cohort. Psoriasiform and seborrheic disease are recorded separately.

Impaired Specific Antibody Response FREQUENT HP:0012475

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Despite generally normal Ig concentrations, CARMIL2-deficient individuals displayed abnormally weak-specific Ab responses to protein-based booster vaccines, as 23/32 (72%) and 15/15 (100%) of the patients had low titers or no Abs against tetanus and diphtheria toxoid, respectively (Fig. 6 B and..."

Responses to protein vaccines can be poor despite normal serum IgG: low or absent tetanus antibodies occurred in 23/32 (72%), and diphtheria antibodies in 15/15 tested patients. These denominators describe tested subgroups.

Psoriasiform Dermatitis FREQUENT HP:0003765

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"In addition, psoriasis-like lesions were noted in 33/87 (38%) individuals."

Psoriasis-like lesions occurred in 33/87 patients (38%) and are distinct from the atopic dermatitis count.

Seborrheic Dermatitis HP:0001051

Show evidence (1 reference)

PMID:27896283 SUPPORT PRIMARY RESULT Human Clinical

"The patient has a variable degree of psoriatic lesions and seborrheic dermatitis, mainly affecting the scalp, and recurrent bacterial skin infections, occurring in the dermatitis lesions."

Seborrheic scalp disease is reported in the Norwegian founder kindreds; a population frequency is not established.

Recurrent Lower Respiratory Tract Infections FREQUENT HP:0002783

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Recurrent upper and lower respiratory tract infections were noted in 53/87 (61%) and 53/87 (61%) CARMIL2-deficient individuals, respectively (Fig. 7 E)."

Recurrent lower respiratory infections occurred in 53/87 (61%).

Bacterial Skin Abscesses FREQUENT Cutaneous abscess HP:0031292

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

Bacterial cutaneous abscesses occurred in 26/87 (30%).

Severe Cytomegalovirus Infection OCCASIONAL HP:0031692

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"In addition to CMV pneumonia, five cases of CMV-induced retinitis and four cases of CMV colitis were reported, so clinical CMV disease was observed in 11/87 (13%) CARMIL2-deficient individuals."

Clinical CMV disease, including retinitis or colitis, occurred in 11/87 (13%); this is distinct from asymptomatic viral replication.

Food Allergy OCCASIONAL HP:0500093

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Food allergies were reported in 12/87 (14%) and allergic asthma was diagnosed in 33/87 (38%) CARMIL2-deficient individuals."

Food allergy was reported in 12/87 (14%).

Asthma FREQUENT HP:0002099

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Food allergies were reported in 12/87 (14%) and allergic asthma was diagnosed in 33/87 (38%) CARMIL2-deficient individuals."

Asthma occurred in 33/87 (38%) in the large cohort; another cohort showed that demonstrable allergen sensitization is not universal.

Integument 1

Recalcitrant Cutaneous Warts FREQUENT Verrucae HP:0200043

Temporal: CHRONIC

Show evidence (2 references)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"HPV was the most common cutaneous infection (n=7, 47%, P3, P4, P6, P7, P11, P14, P15)."

Seven of 15 had cutaneous HPV disease.

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"Some patients had very persistent and widespread warts (P3 and P4, Fig. 1D), while others had only a few and self-limiting warts (P6, P7, P11, P14, P15)."

The cohort included both persistent and self-limited warts.

Respiratory 1

Bronchiectasis OCCASIONAL HP:0002110

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Bronchiectasis was reported in 12/87 (14%) CARMIL2-deficient individuals."

Bronchiectasis occurred in 12/87 (14%) and can complicate recurrent respiratory infection.

Growth 1

Failure to Thrive FREQUENT HP:0001508

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Failure to thrive was noted in 46/84 (55%) CARMIL2-deficient individuals and was positively associated with GI tract involvement (r = 0.31, P < 0.01)."

Growth faltering affected 46/84 (55%) and was associated with gastrointestinal involvement; infection and other nutritional burdens can also contribute.

Neoplasm 1

EBV-Positive Smooth Muscle Tumor OCCASIONAL Soft tissue neoplasm HP:0031459

Show evidence (2 references)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"EBV+ SMTs were reported in 15/87 (17%) CARMIL2-deficient individuals."

EBV-positive smooth muscle tumors affected 15/87 (17%) clinically characterized patients and can be multifocal. EBV DNA was undetectable in blood in 3/15 tumor cases; a negative blood test does not exclude a tumor.

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"EBV viremia was not detected in 3/15 affected individuals (20%) and an absence of viremia should not, therefore, be regarded as an exclusion criterion for EBV+ SMTs (Magg et al., 2018)."

Blood viral testing can be negative despite tissue-associated tumors.

🧬

Genetic Associations

CARMIL2

Gene: CARMIL2 hgnc:27089 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:28112205 SUPPORT PRIMARY RESULT Human Clinical

Establishes the causal gene, its product, and the biallelic loss-of-function mechanism.

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"Transcript 3 was expressed in HD cells, but RT-PCR and Sanger sequencing identified only transcript 1 in P42 T cell blasts, with the retention of 108 nucleotides of intron 14 (Fig. 1 K)."

RNA analysis explains the isoform-dependent splice consequence.

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"Two individuals displayed a heterozygous reversion to the WT allele (P53, P57), and P1 had a heterozygous somatic missense variant at the site of the mutation (c.1578C>G, p.Cys526Trp) restoring normal splicing and CD28 signaling (Fig. 8, A and B; and Fig."

Somatic repair can restore function in selected T-cell lineages.

💊

Medical Actions

Allogeneic Hematopoietic Cell Transplantation

Action: Allogeneic Hematopoietic Cell Transplantation Ontology label: Allogeneic Hematopoietic Stem Cell Transplantation NCIT:C46089

Platform: Cell therapy

A retrospective series of 17 patients receiving 19 transplants reported 82.4% survival at a median follow-up of 37 months and 61.8% event-free survival. Immune and inflammatory manifestations improved in survivors, but three patients died early and two required repeat HCT for graft failure. Among five patients with EBV-positive tumors, one had complete remission, two partial remission, one stable disease and one progression. Residual immune defects occurred with mixed chimerism. These data support early specialist transplant assessment, while benefit and risk remain individualized.

Mechanism Target:

Reduced Functional CARMIL2 Protein — Donor hematopoiesis supplies cells with functional CARMIL2; it does not repair the recipient germline genotype or guarantee complete immune reconstitution.

Show evidence (3 references)

PMID:42529607 SUPPORT PRIMARY RESULT Human Clinical

"Three patients died during the early posttransplant period (overall survival, 82.4%), and two required a second HCT for graft failure."

The series reports both survival and transplant failures.

PMID:42529607 SUPPORT PRIMARY RESULT Human Clinical

"After HCT, one patient achieved complete remission (P13, 20%), two showed a partial remission (P5 and P7, 40%), one had stable disease (P8, 20%), and one suffered from progressive disease (P1, 20%), contributing to an early multifactorial respiratory failure and subsequent death 1 mo after HCT."

Tumor responses were variable, not universal cure.

PMID:42529607 SUPPORT PRIMARY RESULT Human Clinical

"Overall event-free survival (EFS) was 61.8% (Fig. 1 A), with events defined as death of any cause or graft failure."

Event-free survival accounts for death or graft failure.

Show evidence (4 references)

PMID:42529607 SUPPORT PRIMARY RESULT Human Clinical

"Three patients died during the early posttransplant period (overall survival, 82.4%), and two required a second HCT for graft failure."

The series reports both survival and transplant failures.

PMID:42529607 SUPPORT PRIMARY RESULT Human Clinical

Tumor responses were variable, not universal cure.

PMID:42529607 SUPPORT PRIMARY RESULT Human Clinical

"Overall event-free survival (EFS) was 61.8% (Fig. 1 A), with events defined as death of any cause or graft failure."

Event-free survival accounts for death or graft failure.

+ 1 more reference

Immunoglobulin Replacement Therapy

Action: Immunoglobulin Replacement Therapy Ontology label: Immunoglobulin Therapy NCIT:C62710

Platform: Protein replacement

Immunoglobulin replacement was given to 7/15 patients in a longitudinal cohort because of infections and impaired antibody responses, even when total IgG was not low. Combined prophylaxis and replacement reduced infection frequency observationally. After HCT, no patient in the transplant cohort required replacement beyond 24 months; earlier post-transplant support may still be needed.

Mechanism Target:

Impaired Specific Antibody Production — Immunoglobulin replacement was given to 7/15 patients in a longitudinal cohort because of infections and impaired antibody responses, even when total IgG was not low. Combined prophylaxis and replacement reduced infection frequency observationally. After HCT, no patient in the transplant cohort required replacement beyond 24 months; earlier post-transplant support may still be needed.

Show evidence (2 references)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"Because of recurrent infections and dysgammaglobulinemia with poor antibody responses, five patients (33%, P3, P4, P6, P7, P15) received prophylactic antibiotics and seven patients (47%, P3, P6, P7, P9–11, P15) were commenced on immunoglobulin replacement therapy (IgRT) with one receiving via..."

The primary cohort directly documents intravenous and subcutaneous replacement.

PMID:42529607 SUPPORT PRIMARY RESULT Human Clinical

"Similarly, CD19+ B cell deficiency (<200/μl) was reported only in P14 (+26 mo), and no patient required immunoglobulin replacement therapy (IGRT) beyond 24 mo after HCT."

The full results specify the post-transplant timing.

Show evidence (2 references)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

The primary cohort directly documents intravenous and subcutaneous replacement.

PMID:42529607 SUPPORT PRIMARY RESULT Human Clinical

"Similarly, CD19+ B cell deficiency (<200/μl) was reported only in P14 (+26 mo), and no patient required immunoglobulin replacement therapy (IGRT) beyond 24 mo after HCT."

The full results specify the post-transplant timing.

Antimicrobial Prophylaxis

Action: Antimicrobial Prophylaxis Ontology label: Antibiotic Prophylaxis NCIT:C51993

Platform: Other

Published cohorts used trimethoprim-sulfamethoxazole and, in selected patients, fluconazole. Azithromycin improved chronic rhinosinusitis and productive cough in one patient. Selection depends on infection history and immune assessment; the evidence is observational.

Mechanism Target:

Failure of Cell-Mediated Control of Chronic Viral and Fungal Infection — Published cohorts used trimethoprim-sulfamethoxazole and, in selected patients, fluconazole. Azithromycin improved chronic rhinosinusitis and productive cough in one patient. Selection depends on infection history and immune assessment; the evidence is observational.

Show evidence (2 references)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"P4 was initiated on trimethoprim-sulfamethoxazole, while P6, P7, P9–11, and P15 were on trimethoprim-sulfamethoxazole and fluconazole prophylaxis."

The cohort documents antimicrobial prophylaxis.

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"P3 was on azithromycin prophylaxis, and chronic rhinosinusitis and productive cough benefited from the therapy."

A patient-level respiratory response was reported.

Show evidence (2 references)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"P4 was initiated on trimethoprim-sulfamethoxazole, while P6, P7, P9–11, and P15 were on trimethoprim-sulfamethoxazole and fluconazole prophylaxis."

The cohort documents antimicrobial prophylaxis.

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"P3 was on azithromycin prophylaxis, and chronic rhinosinusitis and productive cough benefited from the therapy."

A patient-level respiratory response was reported.

Topical Treatment of Inflammatory Skin Disease

Action: Topical Treatment of Inflammatory Skin Disease Ontology label: Topical Corticosteroid Therapy NCIT:C122078

Platform: Other

Topical corticosteroids and calcineurin inhibitors have been used for eczema and psoriasiform lesions. Severe or refractory disease requires individualized management.

Mechanism Target:

Atopic Dermatitis — Topical corticosteroids and calcineurin inhibitors have been used for eczema and psoriasiform lesions. Severe or refractory disease requires individualized management.

Show evidence (1 reference)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"Topical corticosteroids and calcineurin inhibitors are effective in managing eczema and psoriatic lesions, and sun protection helped in cases with photosensitive dermatitis16."

The cohort describes topical control of skin disease.

Show evidence (1 reference)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"Topical corticosteroids and calcineurin inhibitors are effective in managing eczema and psoriatic lesions, and sun protection helped in cases with photosensitive dermatitis16."

The cohort describes topical control of skin disease.

Medical Treatment of Inflammatory Bowel Disease

Action: Medical Treatment of Inflammatory Bowel Disease Ontology label: Pharmacotherapy NCIT:C15986

Platform: Other

Mesalamine, corticosteroids and other immunosuppressive or biologic agents have been used, with variable or incomplete responses. Some patients required colectomy after multiple medical therapies failed; infection risks complicate treatment selection.

Mechanism Target:

Inflammatory Bowel Disease — Mesalamine, corticosteroids and other immunosuppressive or biologic agents have been used, with variable or incomplete responses. Some patients required colectomy after multiple medical therapies failed; infection risks complicate treatment selection.

Show evidence (2 references)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"More commonly used options are mesalazine, sulfasalazine, steroids, azathioprine, and infliximab for IBD."

The clinical report summarizes drugs used for intestinal inflammation.

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"Due to unresponsiveness to immunosuppressants, both underwent colectomy, which resolved their symptoms."

Refractory disease prompted surgery in two patients.

Show evidence (2 references)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"More commonly used options are mesalazine, sulfasalazine, steroids, azathioprine, and infliximab for IBD."

The clinical report summarizes drugs used for intestinal inflammation.

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"Due to unresponsiveness to immunosuppressants, both underwent colectomy, which resolved their symptoms."

Refractory disease prompted surgery in two patients.

Colectomy for Refractory Colitis

Action: Colectomy for Refractory Colitis Ontology label: Colectomy NCIT:C15209

Platform: Surgery

Colectomy resolved intestinal symptoms in two medically refractory patients in the longitudinal cohort. It treats severe colonic disease without correcting the systemic immunodeficiency.

Mechanism Target:

Inflammatory Bowel Disease — Colectomy resolved intestinal symptoms in two medically refractory patients in the longitudinal cohort. It treats severe colonic disease without correcting the systemic immunodeficiency.

Show evidence (1 reference)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"Due to unresponsiveness to immunosuppressants, both underwent colectomy, which resolved their symptoms."

Two patients obtained symptomatic control after medical treatment failure.

Show evidence (1 reference)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"Due to unresponsiveness to immunosuppressants, both underwent colectomy, which resolved their symptoms."

Two patients obtained symptomatic control after medical treatment failure.

Correction of Gastrointestinal Stenosis

Action: Correction of Gastrointestinal Stenosis Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Pyloric surgery produced symptom resolution in two affected siblings. Pneumatic dilation partially relieved another sibling’s esophageal stricture. Treatment is guided by anatomical obstruction; these responses do not establish a fibrotic mechanism.

Mechanism Target:

Pyloric Stenosis — Pyloric surgery produced symptom resolution in two affected siblings. Pneumatic dilation partially relieved another sibling’s esophageal stricture. Treatment is guided by anatomical obstruction; these responses do not establish a fibrotic mechanism.

Show evidence (2 references)

url:https://all-imm.com/index.php/aei/article/view/1595/2445 SUPPORT PRIMARY RESULT Human Clinical

"Pyloric stenosis occurred at 6 years and was surgically corrected, resulting in complete resolution."

One twin had complete symptom resolution after surgery.

url:https://all-imm.com/index.php/aei/article/view/1595/2445 SUPPORT PRIMARY RESULT Human Clinical

"At 16 years, he developed progressive dysphagia due to esophageal stricture with associated esophagitis and nodular pangastritis, partially relieved by pneumatic dilation."

Esophageal dilation provided partial relief.

Esophageal Stenosis — Pneumatic dilation partly relieved symptomatic esophageal narrowing.

Show evidence (1 reference)

url:https://all-imm.com/index.php/aei/article/view/1595/2445 SUPPORT PRIMARY RESULT Human Clinical

"At 16 years, he developed progressive dysphagia due to esophageal stricture with associated esophagitis and nodular pangastritis, partially relieved by pneumatic dilation."

The patient report records partial response.

Show evidence (2 references)

url:https://all-imm.com/index.php/aei/article/view/1595/2445 SUPPORT PRIMARY RESULT Human Clinical

"Pyloric stenosis occurred at 6 years and was surgically corrected, resulting in complete resolution."

One twin had complete symptom resolution after surgery.

url:https://all-imm.com/index.php/aei/article/view/1595/2445 SUPPORT PRIMARY RESULT Human Clinical

"At 16 years, he developed progressive dysphagia due to esophageal stricture with associated esophagitis and nodular pangastritis, partially relieved by pneumatic dilation."

Esophageal dilation provided partial relief.

Inhaled and Intranasal Corticosteroids

Action: Inhaled and Intranasal Corticosteroids Ontology label: Pharmacotherapy NCIT:C15986

Platform: Other

Inhaled corticosteroids were used for reversible airway obstruction; intranasal corticosteroids relieved rhinitis in the longitudinal cohort. Asthma may occur without demonstrable allergen sensitization.

Mechanism Target:

Asthma — Inhaled corticosteroids were used for reversible airway obstruction; intranasal corticosteroids relieved rhinitis in the longitudinal cohort. Asthma may occur without demonstrable allergen sensitization.

Show evidence (2 references)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"P3, P6, P7, and P15 were shown to have reversibility on spirometry and were treated with inhaled corticosteroids."

The cohort directly records asthma treatment.

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"P3, P7, and P15 (20% of patients) had rhinitis, with chronic nasal congestion and rhinorrhea, which was sensitive to intranasal corticosteroids."

Rhinitis responded to intranasal corticosteroids.

Rhinitis — Intranasal corticosteroids relieved rhinitis in the cohort.

Show evidence (1 reference)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"P3, P7, and P15 (20% of patients) had rhinitis, with chronic nasal congestion and rhinorrhea, which was sensitive to intranasal corticosteroids."

The cohort records symptom response.

Show evidence (2 references)

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"P3, P6, P7, and P15 were shown to have reversibility on spirometry and were treated with inhaled corticosteroids."

The cohort directly records asthma treatment.

PMID:34287962 SUPPORT PRIMARY RESULT Human Clinical

"P3, P7, and P15 (20% of patients) had rhinitis, with chronic nasal congestion and rhinorrhea, which was sensitive to intranasal corticosteroids."

Rhinitis responded to intranasal corticosteroids.

Interleukin-2 Supplementation

Action: Interleukin-2 Supplementation Ontology label: Pharmacotherapy NCIT:C15986

Platform: Other

Experimental IL-2 supplementation improves stimulated patient-cell CD25 expression, interferon-gamma output and, in some assays, proliferation. Responses vary with patient, cell subset and time point; CD25 induction can remain below control levels. These are in vitro rescue findings, with no demonstrated clinical efficacy.

Mechanism Target:

Reduced Stimulated T Cell Proliferation — Experimental IL-2 supplementation improves stimulated patient-cell CD25 expression, interferon-gamma output and, in some assays, proliferation. Responses vary with patient, cell subset and time point; CD25 induction can remain below control levels. These are in vitro rescue findings, with no demonstrated clinical efficacy.

Show evidence (2 references)

PMID:32201938 SUPPORT PRIMARY RESULT In Vitro

"When cells derived from CARMIL2-deficient patients were treated with IL-2, CD25 and IFN-γ production increased in a dose-dependent manner."

The primary study measured dose-dependent cellular rescue.

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"CD25 upregulation following anti-CD3/CD28 stimulation of PBMCs was also increased by exogenous IL-2, however it did not reach the levels of healthy control cells (Fig."

Not every activation endpoint normalized.

Show evidence (2 references)

PMID:32201938 SUPPORT PRIMARY RESULT In Vitro

"When cells derived from CARMIL2-deficient patients were treated with IL-2, CD25 and IFN-γ production increased in a dose-dependent manner."

The primary study measured dose-dependent cellular rescue.

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"CD25 upregulation following anti-CD3/CD28 stimulation of PBMCs was also increased by exogenous IL-2, however it did not reach the levels of healthy control cells (Fig."

Not every activation endpoint normalized.

Glutamine Supplementation

Action: Glutamine Supplementation Ontology label: Pharmacotherapy NCIT:C15986

Platform: Other

Glutamine improved NF-kB and mTOR signaling in stimulated patient CD4 T cells and increased IL17A RNA. Proliferation improved in two patients with abolished baseline responses, but not in two with partially preserved responses; secreted IL-17 was not significantly increased. No patient-treatment efficacy was established.

Mechanism Target:

Reduced Activated T Cell mTOR Signaling — Glutamine improved NF-kB and mTOR signaling in stimulated patient CD4 T cells and increased IL17A RNA. Proliferation improved in two patients with abolished baseline responses, but not in two with partially preserved responses; secreted IL-17 was not significantly increased. No patient-treatment efficacy was established.

Show evidence (3 references)

PMID:40738287 SUPPORT PRIMARY RESULT In Vitro

"Glutamine supplementation restored NF-κB and mTOR activity, as measured by p-65 and RPS6 phosphorylation, respectively, and upregulated the expression of IL17A in CARMIL2-mutated CD4+ T cells."

The study reports cellular signaling rescue, not a clinical trial.

url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf SUPPORT PRIMARY RESULT In Vitro

"Glutamine supplementation improv ed proliferation only in T cells in which proliferati ve ca - pacity was completely abolished before the treatment (patients 1 and 4) ( Fig 4 , H )."

url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf SUPPORT PRIMARY RESULT In Vitro

"T cells deri ve d from 2 other patients (patients 8 and 9) maintained partial proliferati v e capacity , which was not improv ed by glutamine supplementation ( Fig 4 , H ; Fig E3 , D )."

Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. Two partially responsive patient cultures did not improve.

Show evidence (3 references)

PMID:40738287 SUPPORT PRIMARY RESULT In Vitro

"Glutamine supplementation restored NF-κB and mTOR activity, as measured by p-65 and RPS6 phosphorylation, respectively, and upregulated the expression of IL17A in CARMIL2-mutated CD4+ T cells."

The study reports cellular signaling rescue, not a clinical trial.

url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf SUPPORT PRIMARY RESULT In Vitro

"Glutamine supplementation improv ed proliferation only in T cells in which proliferati ve ca - pacity was completely abolished before the treatment (patients 1 and 4) ( Fig 4 , H )."

url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf SUPPORT PRIMARY RESULT In Vitro

"T cells deri ve d from 2 other patients (patients 8 and 9) maintained partial proliferati v e capacity , which was not improv ed by glutamine supplementation ( Fig 4 , H ; Fig E3 , D )."

Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. Two partially responsive patient cultures did not improve.

Dupilumab for Refractory Dermatitis

Action: Pharmacotherapy NCIT:C15986

Agent: Dupilumab NCIT:C162455

Platform: Monoclonal antibody

Disease-specific experience is limited and mixed. A published metabolic-study case had marked skin worsening after three months of dupilumab; this observation does not support routine efficacy or establish that all patients will worsen.

Mechanism Target:

Atopic Dermatitis — Disease-specific experience is limited and mixed. A published metabolic-study case had marked skin worsening after three months of dupilumab; this observation does not support routine efficacy or establish that all patients will worsen.

Show evidence (1 reference)

url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf REFUTE PRIMARY RESULT Human Clinical

"(H) Deterioration of skin rash of patient 1 after 3 months of treatment with dupilumab."

Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. This case did not demonstrate the intended reduction of dermatitis.

Show evidence (1 reference)

url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf REFUTE PRIMARY RESULT Human Clinical

"(H) Deterioration of skin rash of patient 1 after 3 months of treatment with dupilumab."

Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. Worsening in one patient argues against assuming dermatitis improvement with dupilumab; it does not establish universal harm.

🔬

Diagnosis

Molecular Diagnosis

Identify biallelic pathogenic CARMIL2 variants with sequencing and segregation analysis, interpreting splice consequences against the functional leukocyte transcript. Functional studies are useful for uncertain alleles.

Whole Exome Sequencing NCIT:C101295

Show evidence (1 reference)

PMID:29479355 SUPPORT PRIMARY RESULT Human Clinical

"Through the use of whole exome sequencing and autozygome-guided analysis, we uncovered two mutations not previously reported (p.R50T and p.L846Sfs) in CARMIL2."

Establishes exome sequencing, with autozygosity mapping in consanguineous families, as the diagnostic route.

Immune Phenotyping and Functional Confirmation

Measure memory T cells, Tregs, memory B cells, NK cells, immunoglobulins and vaccine-specific antibodies. CARMIL2 protein expression and stimulated T-cell proliferation or NF-kB assays can establish functional impairment; normal total counts or IgG do not exclude disease.

Flow Cytometry NCIT:C16585

Show evidence (3 references)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

Most patients had normal serum IgG despite immune dysfunction.

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

Specific vaccine responses reveal defects missed by routine immunoglobulin quantification.

PMID:31115454 SUPPORT PRIMARY RESULT In Vitro

"The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency."

Establishes the functional confirmation step that follows the genetic finding.

Consider CARMIL2 Deficiency in Very Early Onset Inflammatory Bowel Disease

Children presenting with very early onset inflammatory bowel disease should be evaluated for an underlying inborn error of immunity, because the immunological diagnosis changes management. CARMIL2 deficiency is one of the monogenic causes reached this way, and the intestinal disease may precede recognition of the immunodeficiency.

Show evidence (1 reference)

PMID:31115454 SUPPORT PRIMARY RESULT Human Clinical

"This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD."

States the diagnostic recommendation this entry records, in the setting where CARMIL2 deficiency is most likely to be missed.

Screening for EBV-Positive Smooth Muscle Tumors

The large cohort recommends whole-body imaging, ideally MRI, to screen for EBV-positive smooth muscle tumors. Blood EBV testing cannot exclude tumors. Tissue evaluation with smooth-muscle markers and EBER establishes tumor association; this recommendation is based on observational evidence.

Magnetic Resonance Imaging NCIT:C16809

Show evidence (2 references)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"It therefore appears important to screen CARMIL2-deficient individuals for the presence of EBV+ SMTs by whole-body imaging techniques, ideally full-body magnetic resonance imaging, because blood tests are unable to detect these tumors."

The primary cohort proposes whole-body MRI because blood testing can miss tumors.

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"EBV viremia was not detected in 3/15 affected individuals (20%) and an absence of viremia should not, therefore, be regarded as an exclusion criterion for EBV+ SMTs (Magg et al., 2018)."

Negative viremia is not an exclusion criterion.

Assessment of Progressive Gastrointestinal Symptoms

Persistent vomiting, gastric stasis or dysphagia warrants assessment for structural narrowing using endoscopy and appropriate imaging. Biopsy distinguishes inflammation, eosinophilic involvement and infection; stenosis does not by itself establish fibrosis.

Gastrointestinal Endoscopy NCIT:C78162

Show evidence (2 references)

url:https://all-imm.com/index.php/aei/article/view/1595/2445 SUPPORT PRIMARY RESULT Human Clinical

"At 16 years, he developed progressive dysphagia due to esophageal stricture with associated esophagitis and nodular pangastritis, partially relieved by pneumatic dilation."

Endoscopy and clinical assessment identified a treatable esophageal narrowing.

url:https://all-imm.com/index.php/aei/article/view/1595/2445 SUPPORT PRIMARY RESULT Human Clinical

"Histopathological confirmation of fibrosis is not available, and imaging findings are nonspecific and do not permit direct assessment of fibrotic changes."

The report expressly limits mechanistic interpretation of the stenosis.

📊

Prevalence

Worldwide

Cases In Literature Ultra Rare

The largest published characterization assembled 89 individuals from 52 unrelated families originating from 23 countries; a 2026 transplantation series puts the cumulative literature count at an estimated 120 patients. No population rate has been estimated, and the disease is reported almost entirely from consanguineous kindreds, so the numbers reflect ascertainment as much as occurrence.

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"We established biological and clinical phenotypes of CARMIL2 deficiency by studying 89 individuals from 52 unrelated families (Table S1) originating from 23 countries."

Gives the individual and family count of the largest published series. No normalized population rate is asserted.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from CARMIL2 Deficiency:

CD28 deficiency

Overlapping Features Isolated CD28 deficiency shares impaired costimulation, warts and low memory T-cell and Treg counts. The reported human phenotype is substantially narrower than CARMIL2 deficiency.

Distinguishing Features

CARMIL2 deficiency has a broader infection and inflammatory phenotype in reported cohorts.
Reduced NK and memory B-cell compartments and poor vaccine responses favor CARMIL2 deficiency, although no single laboratory abnormality is obligatory.
EBV-positive smooth-muscle tumors and intestinal inflammation are characteristic concerns in CARMIL2 deficiency.

Show evidence (3 references)

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs."

The shared features that make the two easy to confuse.

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak."

The discriminating laboratory features.

PMID:36515678 SUPPORT PRIMARY RESULT Human Clinical

"numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease."

The discriminating clinical features, absent from CD28 deficiency.

Very early onset inflammatory bowel disease of other monogenic cause

Overlapping Features Very early onset colitis may reflect several monogenic immune disorders. CARMIL2 testing is particularly relevant when immune dysregulation, viral skin disease or impaired costimulation accompanies intestinal disease.

Distinguishing Features

Failed T cell proliferation and activation specifically on CD3/CD28 co-stimulation points to the CD28 axis rather than to another monogenic IBD gene
Absent or reduced CARMIL2 protein on immunoblot or flow cytometry
Accompanying recalcitrant warts, molluscum contagiosum and dermatitis

Show evidence (2 references)

PMID:31115454 SUPPORT BACKGROUND Human Clinical

"A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes."

Background establishes monogenic immune disease as a differential for very early onset colitis.

PMID:31115454 SUPPORT PRIMARY RESULT In Vitro

"The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency."

The functional test that resolves the differential.

📊

Related Datasets

Dual T cell– and B cell–intrinsic deficiency in humans [CD4+ T cell SubSeries] GEO:GSE169506

Human lymphocyte RNA sequencing includes stimulation experiments comparing healthy controls, CARMIL2-deficient patients and a CD28-deficient comparator. Assay subsets and stimuli differ across samples.

BULK RNA SEQ

PMID:36515678

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"The raw and processed RNA-seq data are available from GEO under SuperSeries accession number GSE169506."

The primary publication supplies the public accession.

🧫

Experimental Models

Patient T Cell Costimulation and Isoform Complementation PRIMARY_CELL_CULTURE

Primary patient T cells stimulated with CD3/CD28 or PMA, with lentiviral re-expression of functional isoform 3. This addresses limitations of PTEN-deficient Jurkat cells.

Cell source

Patient-derived primary cells

Publication

PMID:36515678

Pathograph links

Failure of CD28-Dependent Canonical NF-kB Activation rescues fidelity: moderate Isoform 3 restored NF-kB activation after both stimuli.

Limitations: Cultured-cell rescue does not establish clinical gene-therapy efficacy; isoform 1 did not provide equivalent complementation.

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"Impaired NF-κB activation upon stimulation with PMA and CD3/CD28 was rescued in primary T cells by the transduction of CARMIL2-deficient cells with the WT CARMIL2 isoform 3, but not by transduction with an empty vector (Fig. 4 I)."

Primary-cell genetic rescue identifies functional CARMIL2 dependence.

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

Primary-cell genetic rescue identifies functional CARMIL2 dependence.

CARMIL2-Deficient Jurkat Variant Assays CELL_LINE

Knockout Jurkat cells complemented with wild-type or patient alleles quantify protein abundance and CD28-induced NF-kB activity.

Cell source

Engineered human Jurkat T-cell line

Publication

PMID:36515678

Pathograph links

Failure of CD28-Dependent Canonical NF-kB Activation partially recapitulates fidelity: moderate Patient alleles impaired CD28 signaling in complementation assays.

Limitations: Immortalized Jurkat cells lack PTEN; primary-cell confirmation is important. Overexpression in HEK293T cells does not reproduce all lymphocyte stability defects.

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28."

Functional allele testing establishes impaired costimulation.

Show evidence (1 reference)

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28."

Functional allele testing establishes impaired costimulation.

Patient B Cell Receptor Stimulation PRIMARY_CELL_CULTURE

Patient B cells stimulated with anti-IgM, CD40 ligand or PMA distinguish receptor-specific signaling defects.

Cell source

Patient-derived primary cells

Publication

PMID:27647349

Pathograph links

B Cell Receptor-Proximal NF-kB Signaling Failure recapitulates fidelity: moderate Anti-IgM-induced NF-kB activation is impaired while CD40 responses remain intact.

Limitations: ERK is relatively preserved; this assay does not isolate the full contribution of T-cell help to antibody deficiency.

Show evidence (2 references)

PMID:27647349 SUPPORT PRIMARY RESULT In Vitro

"Interestingly, although anti-IgM Abs induced NF-κB activation in controls, BCR engagement of RLTPR-deficient B cells failed to induce IκBα degradation or phosphorylation of P65."

The experiment identifies selective BCR-to-NF-kB failure.

+ 1 more reference

Show evidence (2 references)

PMID:27647349 SUPPORT PRIMARY RESULT In Vitro

"Interestingly, although anti-IgM Abs induced NF-κB activation in controls, BCR engagement of RLTPR-deficient B cells failed to induce IκBα degradation or phosphorylation of P65."

The experiment identifies selective BCR-to-NF-kB failure.

PMID:27647349 SUPPORT PRIMARY RESULT In Vitro

"These data show that RLTPR-deficient B cells have a partially defective signaling pathway, at least via NF-κB, but an intact CD40 signaling pathway, at least for the readouts tested."

A preserved alternative signaling route bounds the defect.

Patient T Cell Cytoskeleton and Migration Assays PRIMARY_CELL_CULTURE

Cultured patient T cells show altered microtubule organization, leading-edge actin distribution and migration directionality.

Cell source

Patient-derived primary cells

Publication

PMID:28112205

Pathograph links

Perturbed T Cell Cytoskeletal Organization partially recapitulates fidelity: moderate Patient-cell assays support a directional migration defect despite increased spontaneous speed.

Limitations: Total F-actin, LFA1 and CXCR4 were preserved. Assays do not establish the contribution to infection or tumor risk.

Show evidence (1 reference)

PMID:28112205 SUPPORT PRIMARY RESULT In Vitro

"Although migrating with increased speed that resulted in higher accumulated migratory distance (Supplementary Fig. 7h), CARMIL2-deficient T-cell migration was less orientated with a markedly decreased directness (Fig. 8h) and reduced Euclidean distance (Supplementary Fig. 7i,j)."

Directional movement was measured in patient-cell assays.

Show evidence (1 reference)

PMID:28112205 SUPPORT PRIMARY RESULT In Vitro

Directional movement was measured in patient-cell assays.

Patient T Cells in Dense Three-Dimensional Collagen PRIMARY_CELL_CULTURE

A later study assessed morphology during migration in collagen at approximately three times the earlier concentration.

Cell source

Patient-derived primary cells

Publication

PMID:34287962

Pathograph links

Perturbed T Cell Cytoskeletal Organization fails to recapitulate fidelity: moderate Cells had normal morphology in this assay.

Limitations: The negative morphology result does not refute every prior velocity, microtubule or chemotaxis endpoint; matrix density and assay outputs differ.

Show evidence (1 reference)

PMID:34287962 SUPPORT PRIMARY RESULT In Vitro

"CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix."

Patient T cells retained normal morphology in high-density collagen.

Show evidence (1 reference)

PMID:34287962 SUPPORT PRIMARY RESULT In Vitro

"CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix."

Patient T cells retained normal morphology in high-density collagen.

Patient NK Cell K562 Degranulation Assay CO_CULTURE

Patient NK cells challenged with K562 targets before and after IL-2 pretreatment.

Cell source

Patient-derived primary cells

Publication

PMID:28112205

Pathograph links

Reduced Natural Killer Cell Degranulation recapitulates fidelity: moderate K562-induced degranulation and NKG2D expression were reduced.

Limitations: This assay does not directly test EBV-positive smooth-muscle tumor killing; IL-2 pretreatment abolished measured differences.

Show evidence (2 references)

PMID:28112205 SUPPORT PRIMARY RESULT In Vitro

"NK-cell degranulation in response to co-incubation with the erythroleukemic cell line K562 was impaired and accompanied by a decreased expression of NKG2D."

The target-cell assay shows impaired NK degranulation.

+ 1 more reference

Show evidence (2 references)

PMID:28112205 SUPPORT PRIMARY RESULT In Vitro

"NK-cell degranulation in response to co-incubation with the erythroleukemic cell line K562 was impaired and accompanied by a decreased expression of NKG2D."

The target-cell assay shows impaired NK degranulation.

PMID:28112205 SUPPORT PRIMARY RESULT In Vitro

"NK cell and CD8 T-cell pre-culturing with IL-2 abrogated the observed differences in degranulation and NKG2D expression (Fig. 6)."

The phenotype is stimulus- and treatment-dependent.

IL-2 Rescue of Patient T Cells PRIMARY_CELL_CULTURE

Exogenous IL-2 added to activated patient lymphocytes improves selected activation and proliferation readouts.

Cell source

Patient-derived primary cells

Publication

PMID:32201938

Pathograph links

Reduced Stimulated T Cell Proliferation rescues fidelity: moderate Proliferation improves in responsive patient cultures.

Limitations: Some patients had normal baseline proliferation; rescue is endpoint-specific, and Treg expansion was not established.

Show evidence (2 references)

PMID:32201938 SUPPORT PRIMARY RESULT In Vitro

"In conclusion, we found that IL-2 rescued T cell activation and proliferation in CARMIL2-deficient patients."

The primary study reports in vitro rescue.

+ 1 more reference

Show evidence (2 references)

PMID:32201938 SUPPORT PRIMARY RESULT In Vitro

"In conclusion, we found that IL-2 rescued T cell activation and proliferation in CARMIL2-deficient patients."

The primary study reports in vitro rescue.

PMID:36515678 SUPPORT PRIMARY RESULT In Vitro

"CD25 upregulation following anti-CD3/CD28 stimulation of PBMCs was also increased by exogenous IL-2, however it did not reach the levels of healthy control cells (Fig."

CD25 remained below healthy-control levels in the later study.

Patient CD4 T Cell Metabolic Profiling and Glutamine Rescue PRIMARY_CELL_CULTURE

RNA sequencing, metabolite profiling and signaling assays after activation show altered metabolic programs and response to added glutamine. Nine patients were recruited, with smaller subsets in each assay.

Cell source

Patient-derived primary cells

Publication

PMID:40738287

Pathograph links

Impaired Activation-Induced T Cell Metabolic Reprogramming partially recapitulates fidelity: moderate Patient cells show altered metabolic transcripts and metabolite abundance.

Limitations: RNA sequencing used four patients and three controls; metabolomics used six and eight. Abundance is not metabolic flux or uptake.

Show evidence (2 references)

PMID:40738287 SUPPORT PRIMARY RESULT In Vitro

"RNA sequencing of CD4+ T cells revealed decreased expression of genes associated with metabolic activity, including mTOR signaling, glycolysis, 1-carbon metabolism, and glutamine metabolism."

Metabolic transcriptional changes were measured.

+ 1 more reference

Reduced Activated T Cell mTOR Signaling rescues fidelity: moderate Glutamine increased RPS6 phosphorylation.

Limitations: Only two of four patients in the proliferation assay improved; increased IL17A RNA did not establish increased secreted IL-17 or clinical benefit.

Show evidence (3 references)

PMID:40738287 SUPPORT PRIMARY RESULT In Vitro

"Glutamine supplementation restored NF-κB and mTOR activity, as measured by p-65 and RPS6 phosphorylation, respectively, and upregulated the expression of IL17A in CARMIL2-mutated CD4+ T cells."

The rescue readouts are signaling and transcript expression.

+ 2 more references

Show evidence (2 references)

PMID:40738287 SUPPORT PRIMARY RESULT In Vitro

"RNA sequencing of CD4+ T cells revealed decreased expression of genes associated with metabolic activity, including mTOR signaling, glycolysis, 1-carbon metabolism, and glutamine metabolism."

Metabolic transcriptional changes were measured.

PMID:40738287 SUPPORT PRIMARY RESULT In Vitro

"Whole-cell metabolomics reinforced these results and highlighted glutamine deficiency as a potential driver of the observed metabolic phenotype."

Metabolite profiling provides a second readout.

Autologous EBV Lymphoblastoid Cell and Patient T Cell Coculture CO_CULTURE

Serial coculture tested EBV-responsive T-cell expansion and cytokine output in two patients and healthy controls.

Cell source

Patient peripheral T cells and autologous irradiated EBV-positive lymphoblastoid cells

Publication

PMID:28112205

Pathograph links

Uncontrolled EBV Infection of Smooth Muscle partially recapitulates fidelity: low Patient T cells expanded poorly and lacked IFN-gamma secretion to autologous EBV-positive lymphoblastoid cells.

Limitations: The target cells are lymphoblastoid cells, not infected smooth-muscle cells or tumors. The experiment supports impaired EBV responses but does not reproduce tumor initiation or directly measure tumor killing.

Show evidence (2 references)

PMID:28112205 SUPPORT PRIMARY RESULT In Vitro

"We found that expansion rates of LCL stimulated T-cell lines (TCL) from P2.1 and P2.2 were significantly lower than from HD (Supplementary Fig. 2a)."

Two patient T-cell lines expanded poorly with autologous EBV-positive lymphoblastoid targets.

+ 1 more reference

Show evidence (2 references)

PMID:28112205 SUPPORT PRIMARY RESULT In Vitro

"We found that expansion rates of LCL stimulated T-cell lines (TCL) from P2.1 and P2.2 were significantly lower than from HD (Supplementary Fig. 2a)."

Two patient T-cell lines expanded poorly with autologous EBV-positive lymphoblastoid targets.

PMID:28112205 SUPPORT PRIMARY RESULT In Vitro

"TCL from P2.1 and P2.2 did not secrete IFN-γ on stimulation with autologous LCL but secreted IFN-γ on stimulation with phytohemagglutintin (PHA) (Supplementary Fig. 2b)."

EBV-target stimulation failed to induce normal IFN-gamma output.

🐁

Animal Models

Rltpr bas L432P Mouse

ENU-derived L432P mice show defective CD28 costimulation, reduced Tregs and impaired T-dependent antibody responses. Reduced protein dosage alone does not explain the phenotype because heterozygous-null mice with similar protein abundance retain responses.

Species

Mouse

Genotype

Homozygous Rltpr bas L432P missense allele

Publication

PMID:23793062

Pathograph links

Loss of CARMIL2 Scaffolding of CD28 to CARD11 recapitulates fidelity: high The mutant protein reaches the synapse with CD28 but fails to connect it to protein kinase C-theta and Carma1, which is precisely the scaffolding failure this node describes.

Limitations: The allele is a point mutant from a mutagenesis screen rather than one of the human disease alleles, and the human disease is caused by absent or degraded protein at least as often as by a hypomorphic one. The scaffolding conclusion was subsequently confirmed directly in human T cells, so the model is not the sole support for this node.

Readouts

CD28 connection to protein kinase C-theta and Carma1

Whether CD28 engagement at the immunological synapse recruits its two key downstream effectors in mutant versus wild-type T cells.

Direction: ABOLISHED

Interpretation: Loss of the connection with preserved colocalization is the observation that identifies the lesion as scaffolding rather than localization.

Show evidence (1 reference)

PMID:23793062 SUPPORT PRIMARY RESULT Model Organism

Reports the measurement behind this readout.

Show evidence (1 reference)

PMID:23793062 SUPPORT PRIMARY RESULT Model Organism

Supports treating this model as informative for the scaffolding node.

Regulatory T Cell Deficit recapitulates fidelity: high The model has reduced Treg development; residual Tregs are present.

Limitations: The mouse does not reproduce the mucocutaneous and intestinal inflammation that the human Treg deficit is invoked to explain, so it supports the cellular node without testing the edge that runs from it to tissue disease.

Show evidence (1 reference)

PMID:23793062 SUPPORT PRIMARY RESULT Model Organism

"We found that Rltpr was a lymphoid cell-specific, actin-uncapping protein essential for costimulation via CD28 and the development of regulatory T cells."

Supports treating the model as informative for the regulatory T cell node.

B Cell Receptor-Proximal NF-kB Signaling Failure fails to recapitulate fidelity: moderate Mouse B-cell proliferative responses and T-independent antibody responses were preserved.

Limitations: The measured mouse endpoints do not reproduce the human selective BCR defect; normal proliferation is not a direct measurement of every NF-kB component.

Show evidence (2 references)

PMID:27647348 SUPPORT PRIMARY RESULT Model Organism

"Mice deprived of functional RLTPR molecules had normal numbers of B cells, and cross-linking of the BCR of such B cells induced their proliferation to the same extent as WT B cells."

Anti-IgM proliferation was preserved.

+ 1 more reference

Show evidence (1 reference)

PMID:23793062 SUPPORT PRIMARY RESULT Model Organism

"We found that Rltpr was a lymphoid cell-specific, actin-uncapping protein essential for costimulation via CD28 and the development of regulatory T cells."

Establishes the model as informative for both the co-stimulation and the regulatory T cell nodes.

Rltpr Null Mouse

Complete Rltpr loss impairs costimulation and reduces regulatory and effector-memory CD4 T cells; not all human immune or inflammatory findings occur.

Species

Mouse

Genotype

Deletion of Rltpr exons 1–3

Publication

PMID:27647348

Pathograph links

Regulatory T Cell Deficit partially recapitulates fidelity: moderate Regulatory-cell abundance is reduced.

Limitations: Residual Tregs remain, CD8 memory is relatively preserved and overt autoimmune inflammation is not reproduced.

Show evidence (1 reference)

PMID:27647348 SUPPORT PRIMARY RESULT Model Organism

"Likewise, the spleens of Rltpr−/− mice had approximately one third as many Foxp3+ T reg cells as WT spleen had (Fig. 3 D)."

The deletion model was used to assess Rltpr-dependent immune phenotypes.

Show evidence (1 reference)

PMID:27647348 SUPPORT PRIMARY RESULT Model Organism

"Likewise, the spleens of Rltpr−/− mice had approximately one third as many Foxp3+ T reg cells as WT spleen had (Fig. 3 D)."

The deletion model was used to assess Rltpr-dependent immune phenotypes.

Rltpr CPI-Motif Mutant Mouse

Selective CPI disruption separates actin-capping-protein interaction from the scaffolding function required for costimulation.

Species

Mouse

Genotype

Capping-protein-binding CPI motif substitutions

Publication

PMID:27647348

Pathograph links

Loss of CARMIL2 Scaffolding of CD28 to CARD11 fails to recapitulate fidelity: moderate Disruption of the CPI motif does not abolish CD28 costimulation or Treg development.

Limitations: This domain-specific separation-of-function mutant is not equivalent to complete CARMIL2 loss.

Show evidence (1 reference)

PMID:27647348 SUPPORT PRIMARY RESULT Model Organism

"Our data demonstrated, however, that the RLTPR CPI motif is dispensable for co-stimulation via CD28 and the development of T reg and effector memory CD4+ T cells."

The negative phenotype shows that capping-protein interaction is dispensable for these outputs.

Show evidence (1 reference)

PMID:27647348 SUPPORT PRIMARY RESULT Model Organism

"Our data demonstrated, however, that the RLTPR CPI motif is dispensable for co-stimulation via CD28 and the development of T reg and effector memory CD4+ T cells."

The negative phenotype shows that capping-protein interaction is dispensable for these outputs.

Carmil2QE gain-of-function knock-in mouse

Carmil2 QE gain-of-function mice form preassembled CARMIL2-CARD11 complexes and can restore many antigen-dependent functions in Cd28-null mice. This is a pathway perturbation, not an autosomal recessive deficiency model.

Species

Mouse

Genotype

Carmil2QE knock-in, modelling a CARMIL2 substitution found in human T cell malignancies

Publication

PMID:40402149

Pathograph links

Loss of CARMIL2 Scaffolding of CD28 to CARD11 perturbs fidelity: moderate A gain-of-function perturbation of the same node the disease loses. It does not model the disease state; it tests, in the opposite direction, whether the CARMIL2-CARD11 complex is the operative element of CD28 co-stimulation.

Limitations: Treg numbers were restored more fully than suppressive activity, which remained about twofold reduced; iNKT development was not rescued. Mouse NK counts were restored, but this does not explain all differences between human CD28 and CARMIL2 deficiencies. Solid-tumor assays did not model EBV-positive smooth-muscle tumors.

Show evidence (1 reference)

PMID:40402149 SUPPORT PRIMARY RESULT Model Organism

"In conclusion, we uncovered the overarching role played by CARMIL2-CARD11 signals among those triggered by CD28 and exploited them to induce potent solid tumor-specific T cell responses in the absence of CD28 ligands and immune checkpoint inhibitors."

The authors' conclusion that CARMIL2-CARD11 is the dominant arm of CD28 signalling, which is the claim this entry's central chain depends on.

Regulatory T Cell Deficit rescues fidelity: moderate The gain-of-function allele restores regulatory-cell numbers in Cd28-null mice.

Limitations: Suppressive function remained about twofold reduced, and iNKT development was not restored.

Show evidence (2 references)

PMID:40402149 SUPPORT PRIMARY RESULT Model Organism

"They had, however, a twofold reduced suppressive activity as compared to those of WT and Carmil2QE mice (Fig. 5 C)."

Cell numbers and suppressive function did not recover equivalently.

+ 1 more reference

Show evidence (1 reference)

PMID:40402149 SUPPORT PRIMARY RESULT Model Organism

"Such ready-made CARMIL2QE-CARD11 complexes also formed in CD28-deficient mice where they unexpectedly induced most of the functions that normally result from CD28 engagement in a manner that remains antigen-dependent."

The epistasis result that makes the model informative for the scaffolding node.

Naturally Occurring Canine CARMIL2 R291Ter

Three dogs with a homozygous nonsense variant had opportunistic or refractory pneumonia and gastrointestinal or skin manifestations. Two had Pneumocystis pneumonia and one had refractory Bordetella pneumonia.

Species

Dog

Genotype

Homozygous CARMIL2 p.R291Ter in Cavalier King Charles Spaniels

Publication

PMID:38535207

Pathograph links

Failure of Cell-Mediated Control of Chronic Viral and Fungal Infection partially recapitulates fidelity: low The naturally occurring canine disorder partially parallels human susceptibility to infection.

Limitations: Protein abundance and lymphocyte function were not measured, so the signaling mechanism is inferred from genotype and clinical parallels. Nine other dogs with Pneumocystis infection lacked the variant.

Show evidence (2 references)

PMID:38535207 SUPPORT PRIMARY RESULT Model Organism

"Here, we report the discovery of a CARMIL2 nonsense variant in three Cavalier King Charles Spaniel dogs with either PCP (n = 2) or refractory Bordetella pneumonia (n = 1)."

The primary veterinary report describes three affected dogs.

+ 1 more reference

Show evidence (2 references)

PMID:38535207 SUPPORT PRIMARY RESULT Model Organism

"Here, we report the discovery of a CARMIL2 nonsense variant in three Cavalier King Charles Spaniel dogs with either PCP (n = 2) or refractory Bordetella pneumonia (n = 1)."

The primary veterinary report describes three affected dogs.

PMID:38535207 SUPPORT PRIMARY RESULT Model Organism

"Future studies to quantify CARMIL2 protein production and delineate the functional implications of this variant on host immunity are warranted."

The authors explicitly identify missing functional measurements.

{ }

Source YAML

click to show

name: CARMIL2 Deficiency
creation_date: '2026-09-03T00:00:00Z'
category: Mendelian
disease_term:
preferred_term: CARMIL2 deficiency
term:
id: MONDO:0029134
label: severe combined immunodeficiency due to CARMIL2 deficiency
synonyms:
- severe combined immunodeficiency due to CARMIL2 deficiency
- RLTPR deficiency
- CARMIL2 (RLTPR) deficiency
- IMD58
- immunodeficiency 58
description: >-
CARMIL2 deficiency is an autosomal recessive combined immunodeficiency caused by biallelic loss-of-function
variants in CARMIL2 (formerly RLTPR). Defective CARMIL2-dependent signaling impairs CD28 costimulation,
T cell activation and immune memory; additional B cell and natural killer cell abnormalities broaden
the phenotype beyond isolated CD28 deficiency. Recurrent respiratory and mucocutaneous infections, dermatitis,
intestinal inflammation, growth failure and EBV-positive smooth muscle tumors occur with variable severity.
Symptoms usually begin in infancy, but later onset occurs. Allogeneic hematopoietic cell transplantation
can restore immunity and improve inflammatory disease and some tumors, with substantial transplant risks.
parents:
- Combined immunodeficiency
- Inborn error of immunity
- Primary immunodeficiency
classifications:
harrisons_chapter:
- classification_value: IMMUNE_RHEUMATOLOGIC
notes: >-
CARMIL2 deficiency is an inborn error of immunity, curated under disorders of the immune system.
evidence:
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Human CARMIL2-deficiency is therefore an autosomal recessive primary immunodeficiency disorder
associated with defective CD28-mediated TCR co-signalling and impaired cytoskeletal dynamics.
explanation: >-
Establishes the condition as a primary immunodeficiency, which places it in the immunology/rheumatology
grouping.
quote_role: PRIMARY_RESULT
iuis_category:
classification_value: combined immunodeficiency
notes: >-
Combined immunodeficiency affecting cellular immunity and specific antibody responses; total lymphocyte
counts and serum immunoglobulins may be preserved.
evidence:
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Human RLTPR deficiency is a CID affecting at least the CD28-responsive pathway in T cells and
the BCR-responsive pathway in B cells.
explanation: >-
States the combined-immunodeficiency classification and names both the cellular and the humoral
arm, which is what the IUIS combined immunodeficiency table covers.
quote_role: PRIMARY_RESULT
- reference: PMID:32625199
reference_title: A Novel Pathogenic Variant in CARMIL2 (RLTPR) Causing CARMIL2 Deficiency and EBV-Associated Smooth Muscle Tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CARMIL2 deficiency is a rare combined immunodeficiency (CID) characterized by defective CD28-mediated
T cell co-stimulation, altered cytoskeletal dynamics, and susceptibility to Epstein Barr Virus
smooth muscle tumors (EBV-SMTs).
explanation: >-
Independent statement of the same classification, from a later case report.
quote_role: PRIMARY_RESULT
mappings:
mondo_mappings:
- term:
id: MONDO:0029134
label: severe combined immunodeficiency due to CARMIL2 deficiency
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: >-
The exact MONDO concept includes CARMIL2 deficiency and immunodeficiency 58. The entry follows the
clinical literature in using CARMIL2 deficiency; the canonical MONDO label is retained in the binding
and synonyms.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Biallelic loss-of-function variants cause disease, usually in homozygous individuals but also in compound
heterozygotes. In the 89-person ascertained cohort, the Results section reported 95% penetrance by
age 10 and symptom onset from birth to age 22; this qualifies the abstract statement of full penetrance
by age 10. Somatic reversion can modify severity.
expressivity: VARIABLE
evidence:
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Human CARMIL2-deficiency is therefore an autosomal recessive primary immunodeficiency disorder associated
with defective CD28-mediated TCR co-signalling and impaired cytoskeletal dynamics.
explanation: States the autosomal recessive mode of inheritance directly.
quote_role: PRIMARY_RESULT
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Penetrance reached 95% at 10 yr of age (Fig. 7 A).
explanation: The detailed Results give age-dependent cohort penetrance, rather than establishing complete population penetrance.
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: 'Median age at symptom onset was 1 yr (range: 0–22 yr; mean: 2.8 yr).'
explanation: Symptom onset extended into adulthood.
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes.
explanation: >-
Documents one identified source of variable expressivity within the same recessive genotype.
quote_role: PRIMARY_RESULT
pathophysiology:
- name: CARMIL2 Coding Substitutions
description: Biallelic coding substitutions include missense alleles and premature termination variants. Their effects must be interpreted using the relevant transcript and cellular assay.
biological_scale: MOLECULAR
evidence:
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: A1, A2, and A3 carry a homozygous nucleotide substitution (T>G) at position 1,115 in exon 14 of RLTPR, resulting in the replacement of a highly conserved leucine residue by an arginine (L372R) in the leucine-rich repeat (LRR) domain (Fig. 1, d and e; and Fig.
explanation: The founding kindred carried a homozygous coding missense substitution.
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: B1 and B2 carry a nucleotide substitution (C>T) at position 2,557 in exon 25, resulting in the replacement of a glutamine residue by a stop codon (Q853X; Fig. 1, d and e).
explanation: A separate coding substitution introduces a premature stop.
role: trigger
gene: &id001
preferred_term: CARMIL2
term:
id: hgnc:27089
label: CARMIL2
genetic_context:
gene: *id001
variant_type: single nucleotide variant
genomic_contexts:
- coding sequence
downstream:
- target: Reduced Functional CARMIL2 Protein
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The physical alteration compromises the encoded gene product through the documented molecular consequence.
mechanism_confidence: ESTABLISHED
- name: CARMIL2 Coding Deletions
description: Coding deletions can alter the reading frame or remove amino acids in frame; a reported 13-base deletion reduced RNA and detectable protein.
biological_scale: MOLECULAR
evidence:
- reference: PMID:29479355
reference_title: Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: After subjecting the exome capture data to all filters only one variant remained, a homozygous 13bp frameshift deletion in CARMIL2 predicted to cause premature truncation of the protein shortly downstream of its midpoint (NM_001013838.1:c.2536_2548del:p.L846Sfs*36) (Figure 1E).
explanation: Coding deletions can alter the reading frame or remove amino acids in frame; a reported 13-base deletion reduced RNA and detectable protein.
role: trigger
gene: *id001
genetic_context:
gene: *id001
variant_type: deletion
genomic_contexts:
- coding sequence
downstream:
- target: Reduced Functional CARMIL2 Protein
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The physical alteration compromises the encoded gene product through the documented molecular consequence.
mechanism_confidence: ESTABLISHED
- name: CARMIL2 Coding Insertions
description: A homozygous single-base insertion c.489insG was reported in affected patients and predicts premature termination; this is physically an insertion.
biological_scale: MOLECULAR
evidence:
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: The c.489insG and c.871+1G>T CARMIL2 mutations were confirmed by Sanger sequencing (see Supplemantary Table 5 for primer information).
explanation: A homozygous single-base insertion c.489insG was reported in affected patients and predicts premature termination; this is physically an insertion.
role: trigger
gene: *id001
genetic_context:
gene: *id001
variant_type: insertion
genomic_contexts:
- coding sequence
downstream:
- target: Reduced Functional CARMIL2 Protein
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The physical alteration compromises the encoded gene product through the documented molecular consequence.
mechanism_confidence: ESTABLISHED
- name: CARMIL2 Intronic Splice Substitutions
description: Intronic substitutions disrupt splicing. A variant formerly annotated p.Arg385Thr in isoform 1 is intronic c.1149+5G>C in the predominant functional isoform 3.
biological_scale: MOLECULAR
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: This G>C substitution was predicted to affect the splicing of transcripts 2 and 3 at position c.1149 + 5 (Fig. 1 I).
explanation: Transcript-aware annotation identifies the intronic splice alteration.
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Transcript 3 was expressed in HD cells, but RT-PCR and Sanger sequencing identified only transcript 1 in P42 T cell blasts, with the retention of 108 nucleotides of intron 14 (Fig. 1 K).
explanation: Patient RNA confirms retention of the affected intron segment.
role: trigger
gene: *id001
genetic_context:
gene: *id001
variant_type: single nucleotide variant
genomic_contexts:
- intron
downstream:
- target: Abnormal CARMIL2 RNA Processing
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The physical alteration compromises the encoded gene product through the documented molecular consequence.
mechanism_confidence: ESTABLISHED
- name: CARMIL2 Exonic Splice Substitutions
description: Exonic substitutions, including synonymous alleles, can create abnormal splice donors; a synonymous annotation does not imply normal RNA processing.
biological_scale: MOLECULAR
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: One missense (c.871G>C, p.Gly291Arg) and two synonymous (c.1128C>T and c.1578C>T) variants were also predicted to affect mRNA splicing.
explanation: Exonic missense and synonymous substitutions affect splicing.
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: CARMIL2 mRNA levels were also very low in T cell blasts from individuals with the c.1812-7G>A (P31), and c.1578C>T (P1) alleles, consistent with nonsense-mediated mRNA decay (Fig.
explanation: Some splice-altered transcripts are reduced.
role: trigger
gene: *id001
genetic_context:
gene: *id001
variant_type: single nucleotide variant
genomic_contexts:
- coding sequence
downstream:
- target: Abnormal CARMIL2 RNA Processing
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The physical alteration compromises the encoded gene product through the documented molecular consequence.
mechanism_confidence: ESTABLISHED
- name: Abnormal CARMIL2 RNA Processing
description: Patient RNA and minigene studies demonstrate exon skipping, intron retention or cryptic donor use. Some resulting transcripts are reduced, consistent with nonsense-mediated decay; decay is allele-specific and is not established for every premature stop.
biological_scale: MOLECULAR
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Transcript 3 was expressed in HD cells, but RT-PCR and Sanger sequencing identified only transcript 1 in P42 T cell blasts, with the retention of 108 nucleotides of intron 14 (Fig. 1 K).
explanation: RNA assays resolve the intronic effect of the transcript-dependent c.1149+5G>C allele.
- reference: PMID:29479355
reference_title: Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: To check this we performed real-time RT-PCR on patient lymphoblastoid RNA and observed a highly significant drop of >75% in CARMIL2 expression levels for the F1 proband versus healthy controls (p < 0.0001).
explanation: Reduced mutant RNA supports degradation for this frameshift allele; direct NMD inhibition was not tested.
gene: *id001
downstream:
- target: Reduced Functional CARMIL2 Protein
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Abnormal transcripts can encode unstable or truncated products, or reduce protein dosage.
mechanism_confidence: ESTABLISHED
- name: Reduced Functional CARMIL2 Protein
description: Patient cells generally contain markedly reduced or absent functional CARMIL2. Missense stability differs between overexpression systems and lymphocytes. The Q853X transcript was not substantially degraded, and the available C-terminal antibody could not establish endogenous truncated-protein abundance; complete absence is therefore not universal.
biological_scale: MOLECULAR
evidence:
- reference: PMID:29479355
reference_title: Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Similarly there was a loss of detectable CARMIL2 for the F3 patients, indicating that the p.R50T missense mutation was leading to gross instability of the protein.
explanation: Patient lymphoblastoid cells carrying p.R50T lacked detectable protein.
- reference: PMID:29479355
reference_title: Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: It is worth noting, however, that the CARMIL2 band intensity varied considerably between our normal controls, and therefore residual protein expression (as well as weak expression of a truncated form) in our patients cannot be ruled out.
explanation: The primary authors acknowledge antibody/sensitivity limitations.
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: All the cells tested contained very little CARMIL2 protein, if any.
explanation: Patient-cell testing across the available alleles demonstrated low or absent protein.
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: In contrast, higher or normal mRNA levels were observed in herpesvirus saimiri–transformed T cell lines (T-saimiri cells) of A1 and B1, respectively, as compared with healthy controls, suggesting that the nonsense mutation is not associated with significant nonsense-mediated mRNA decay (Fig. 3 b).
explanation: Q853X does not establish a universal NMD mechanism.
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Unfortunately, none of the commercially available Abs recognizing the N-terminal domain of RLTPR detected endogenous RLTPR in control cells (not depicted).
explanation: The endogenous truncated protein could not be assessed with the available N-terminal antibodies.
gene: *id001
downstream:
- target: Loss of CARMIL2 Scaffolding of CD28 to CARD11
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Loss of functional CARMIL2 impairs assembly of the CD28-associated signaling scaffold.
- target: B Cell Receptor-Proximal NF-kB Signaling Failure
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A second, CD28-independent consequence of the same lesion: patient B cells fail to activate NF-kB
on B cell receptor stimulation, so the humoral defect is not solely downstream of the T cell defect.
- target: Perturbed T Cell Cytoskeletal Organization
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Patient-cell assays link deficiency to context-dependent cytoskeletal organization and directional
migration defects.
- target: Reduced Natural Killer Cell Count
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
NK lymphopenia is variable. Mouse genetic experiments implicate CARMIL2/CD28 signaling in NK homeostasis,
but the human cellular route remains unresolved.
- target: Reduced Natural Killer Cell Degranulation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Patient-cell studies associate functional CARMIL2 loss with this readout; the intervening molecular route is incompletely resolved.
- target: Reduced Activated T Cell ASCT2 Abundance
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Patient-cell studies associate functional CARMIL2 loss with this readout; the intervening molecular route is incompletely resolved.
- target: Impaired Activation-Induced T Cell Metabolic Reprogramming
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Patient-cell studies associate functional CARMIL2 loss with this readout; the intervening molecular route is incompletely resolved.
- target: Reduced Activated T Cell mTOR Signaling
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Patient-cell studies associate functional CARMIL2 loss with this readout; the intervening molecular route is incompletely resolved.
mechanism_confidence: ESTABLISHED
- name: Loss of CARMIL2 Scaffolding of CD28 to CARD11
description: >-
CARMIL2 couples CD28-associated signaling to CARD11/CARMA1. Its scaffolding role is separable from
capping-protein binding: experimentally disrupting the CPI motif preserves CD28 costimulation in mice.
role: mediator
biological_scale: MOLECULAR
molecular_functions:
- preferred_term: CD28-to-CARD11 scaffolding activity
term:
id: GO:0030674
label: protein-macromolecule adaptor activity
modifier: LOSS_OF_FUNCTION
evidence:
- reference: PMID:27647348
reference_title: The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Here, using affinity purification followed by mass spectrometry analysis, we showed that RLTPR acts
as a scaffold, bridging CD28 to the CARD11/CARMA1 cytosolic adaptor and to the NF-κB signaling pathway,
and identified proteins not found before within the CD28 signaling pathway.
explanation: >-
Identifies the scaffolding function this node stands for, and the two partners it bridges.
quote_role: PRIMARY_RESULT
- reference: PMID:27647348
reference_title: The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Although RLTPR is thought to function as an actin-uncapping protein, this property was dispensable
for CD28 co-stimulation in both mouse and human.
explanation: >-
The reason the pathograph routes co-stimulation failure through scaffolding rather than through
the actin-uncapping activity, and the reason the cytoskeletal node is kept off this chain.
quote_role: PRIMARY_RESULT
- reference: PMID:23793062
reference_title: The lymphoid lineage-specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
However, the connection between CD28 and protein kinase C-θ and Carma1, two key effectors of CD28
costimulation, was abrogated in T cells expressing mutant Rltpr, and CD28 costimulation did not
occur in those cells.
explanation: >-
The mouse experiment that established the broken connection, at the level of the specific effectors.
Human confirmation is carried by the two preceding items.
quote_role: PRIMARY_RESULT
downstream:
- target: Failure of CD28-Dependent Canonical NF-kB Activation
causal_link_type: DIRECT
description: >-
With the bridge gone, CD28 engagement no longer reaches NF-kB.
mechanism_confidence: ESTABLISHED
- name: Failure of CD28-Dependent Canonical NF-kB Activation
description: >-
CD28 costimulation fails to enhance canonical NF-kB activation appropriately. TCR-proximal signaling
and several AP-1/NFAT outputs are retained. Impaired PMA-induced NF-kB activation in primary patient
T cells also demonstrates a CARMIL2 requirement beyond engagement of CD28 itself.
role: central_effector
biological_scale: CELLULAR
cell_types:
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
biological_processes:
- preferred_term: T cell costimulation
term:
id: GO:0031295
label: T cell costimulation
modifier: LOSS_OF_FUNCTION
- preferred_term: CD28-dependent canonical NF-kB activation
term:
id: GO:0043123
label: positive regulation of canonical NF-kappaB signal transduction
modifier: DECREASED
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1
and NFAT activation in T cells stimulated via CD28.
explanation: >-
Establishes both halves of this node across the whole allelic series: the canonical NF-kB arm fails,
and the AP-1 and NFAT arms do not.
quote_role: PRIMARY_RESULT
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Their CD4+ T cells do not respond to CD28 stimulation.
explanation: The functional readout in patient cells.
quote_role: PRIMARY_RESULT
- reference: PMID:29479355
reference_title: Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
CD3/CD28 signaling impairment was evidenced by reduced proliferative response to stimulation.
explanation: >-
Independent replication of the co-stimulation defect as a proliferation readout in a separate cohort.
quote_role: PRIMARY_RESULT
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Impaired NF-κB activation upon stimulation with PMA and CD3/CD28 was rescued in primary T cells by the transduction of CARMIL2-deficient cells with the WT CARMIL2 isoform 3, but not by transduction with an empty vector (Fig. 4 I).
explanation: Primary-cell isoform-3 complementation restores both CD28-dependent and PMA-stimulated responses.
downstream:
- target: Regulatory T Cell Deficit
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The observed immune defect can contribute to this consequence, but the complete cellular and tissue
route is not established.
- target: Memory T Cell Deficit
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The observed immune defect can contribute to this consequence, but the complete cellular and tissue
route is not established.
- target: Impaired Specific Antibody Production
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Antibody responses are T-cell-dependent, so loss of CD4+ helper output is one route to the humoral
defect. It is not the only one - see the B cell receptor node.
- target: Impaired CD3/CD28-Induced T Cell Proliferation
causal_link_type: DIRECT
description: >-
The unresponsiveness of patient CD4+ T cells to CD28 stimulation is the direct functional readout
of this signalling failure.
evidence:
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Their CD4+ T cells do not respond to CD28 stimulation.
explanation: Documents the failure of patient CD4+ T cells to respond to CD28 stimulation.
quote_role: PRIMARY_RESULT
- target: Reduced T Cell Interleukin-2 Production
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Impaired costimulation reduces induction of IL-2.
- target: Altered Activated T Cell Survival Program
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Deficient costimulation is associated with this altered T-cell program.
- target: Impaired T Follicular Helper Cell Support
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Deficient costimulation is associated with this altered T-cell program.
- target: Reduced CD25 Induction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Costimulation-dependent activation fails to induce normal CD25 expression.
mechanism_confidence: ESTABLISHED
- name: Regulatory T Cell Deficit
description: >-
Circulating regulatory T cell numbers are substantially reduced, with low CD25 and CTLA4 expression
in studied cohorts. Impaired generation and maintenance contribute to loss of immune regulation; residual
Tregs are not universally absent.
role: mediator
biological_scale: CELLULAR
cell_types:
- preferred_term: FOXP3+ regulatory T cell
term:
id: CL:0000815
label: regulatory T cell
biological_processes:
- preferred_term: regulatory T cell differentiation
term:
id: GO:0045066
label: regulatory T cell differentiation
modifier: DECREASED
evidence:
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These patients lack regulatory T cells without evidence of organ-specific autoimmunity, and have
defective CD28 co-signalling associated with impaired T-cell activation, differentiation and function,
as well as perturbed cytoskeletal organization associated with T-cell polarity and migration disorders.
explanation: >-
Establishes the Treg deficit and, importantly, its dissociation from organ-specific autoimmunity.
quote_role: PRIMARY_RESULT
- reference: PMID:32625199
reference_title: A Novel Pathogenic Variant in CARMIL2 (RLTPR) Causing CARMIL2 Deficiency and EBV-Associated Smooth Muscle Tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
FOXP3+ regulatory T cells (Treg) were also quantitatively decreased, and furthermore CD25 expression
within the Treg subset was substantially reduced.
explanation: >-
Adds the qualitative defect within the surviving Treg compartment to the quantitative one.
quote_role: PRIMARY_RESULT
- reference: PMID:23793062
reference_title: The lymphoid lineage-specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We found that Rltpr was a lymphoid cell-specific, actin-uncapping protein essential for costimulation
via CD28 and the development of regulatory T cells.
explanation: >-
The mouse genetics that predicted the human Treg deficit; kept distinct from the two human observations
above by `evidence_source`.
quote_role: PRIMARY_RESULT
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Furthermore, we also evaluated the induction of CTLA4 at baseline and after anti-CD2, anti-CD3 and anti-CD28 stimulation, which resulted in reduced levels compared to healthy controls (p<0.0001, p<0.0001, respectively, Fig. 3D).
explanation: Reduced CTLA4 expression is an additional regulatory-cell abnormality.
downstream:
- target: Mucocutaneous and Intestinal Immune Dysregulation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Loss of regulatory T cells is the standing explanation for the dermatitis and inflammatory bowel
disease, but the intermediate steps between the Treg deficit and the specific tissue inflammation
have not been dissected in this disease.
- target: Decreased Regulatory T Cell Proportion
causal_link_type: DIRECT
description: >-
The measured fall in circulating CD4+ regulatory T cells is the direct laboratory expression of
this deficit.
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs.
explanation: Reports the low circulating Treg counts that this node predicts.
quote_role: PRIMARY_RESULT
mechanism_confidence: ESTABLISHED
- name: Memory T Cell Deficit
description: >-
Reduced CD4+ and CD8+ memory T cell compartments accompany impaired costimulation. Both deficient
expansion and maintenance are plausible contributors; total T cell numbers may remain normal.
role: mediator
biological_scale: CELLULAR
cell_types:
- preferred_term: memory T cell
term:
id: CL:0000813
label: memory T cell
biological_processes:
- preferred_term: memory T cell differentiation
term:
id: GO:0043379
label: memory T cell differentiation
modifier: DECREASED
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood
counts of CD4+ and CD8+ memory T cells and CD4+ TREGs.
explanation: >-
Quantifies the memory T cell deficit and, in the same sentence, marks it as one of the features
shared with CD28 deficiency.
quote_role: PRIMARY_RESULT
- reference: PMID:29479355
reference_title: Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Immunophenotyping revealed that patient Treg counts were significantly depressed, and that CD4+
T cells were heavily skewed towards the naïve status.
explanation: >-
The naive skew is the mirror image of the memory deficit, measured in an independent cohort.
quote_role: PRIMARY_RESULT
downstream:
- target: Failure of Cell-Mediated Control of Chronic Viral and Fungal Infection
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The observed immune defect can contribute to this consequence, but the complete cellular and tissue
route is not established.
- target: Decreased Memory T Cell Proportion
causal_link_type: DIRECT
description: >-
The measured fall in CD4+ and CD8+ memory T cell counts is the direct laboratory expression of this
deficit.
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs.
explanation: Reports the low memory T cell counts that this node predicts.
quote_role: PRIMARY_RESULT
mechanism_confidence: ESTABLISHED
- name: Failure of Cell-Mediated Control of Chronic Viral and Fungal Infection
description: >-
Deficient T-cell activation, memory and effector output, together with variable NK dysfunction, compromise
antimicrobial control. The contributions of individual immune abnormalities vary by pathogen and are
not fully resolved.
role: mediator
biological_scale: ORGANISM
biological_processes:
- preferred_term: T cell mediated immunity
term:
id: GO:0002456
label: T cell mediated immunity
modifier: DECREASED
evidence:
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal
infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis.
explanation: >-
Sets out the breadth of the infection burden, including the mycobacterial and mucosal-fungal infections
that mark a Th1/Th17 defect.
quote_role: PRIMARY_RESULT
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory
bowel disease.
explanation: >-
The cohort-scale statement of the infection burden, alongside the two other defining manifestations.
quote_role: PRIMARY_RESULT
downstream:
- target: Uncontrolled Cutaneous Papillomavirus and Poxvirus Replication
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The observed immune defect can contribute to this consequence, but the complete cellular and tissue
route is not established.
- target: Uncontrolled EBV Infection of Smooth Muscle
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The observed immune defect can contribute to this consequence, but the complete cellular and tissue
route is not established.
- target: Recurrent Mucocutaneous Candidiasis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The observed immune defect can contribute to this consequence, but the complete cellular and tissue
route is not established.
- target: Recurrent Infections
causal_link_type: DIRECT
description: >-
The general infection burden is the direct clinical expression of this node.
- target: Recurrent Upper Respiratory Tract Infections
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Combined immune dysfunction increases susceptibility; the individual contribution of each immune compartment varies.
- target: Recurrent Lower Respiratory Tract Infections
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Combined immune dysfunction increases susceptibility; the individual contribution of each immune compartment varies.
- target: Bacterial Skin Abscesses
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Combined immune dysfunction increases susceptibility; the individual contribution of each immune compartment varies.
- target: Severe Cytomegalovirus Infection
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Combined immune dysfunction increases susceptibility; the individual contribution of each immune compartment varies.
- target: Bronchiectasis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Repeated respiratory infection can lead to chronic airway injury.
mechanism_confidence: ESTABLISHED
- name: Uncontrolled Cutaneous Papillomavirus and Poxvirus Replication
description: >-
Impaired cutaneous viral control permits HPV warts and molluscum contagiosum. Lesions can persist
or become widespread, but some are self-limited and onset varies.
role: consequence
biological_scale: TISSUE
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
evidence:
- reference: PMID:27896283
reference_title: A potential founder variant in CARMIL2/RLTPR in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Four patients from three Norwegian families presented with a common skin phenotype of warts, molluscum
contagiosum, and dermatitis since early childhood, and various other immunological features.
explanation: >-
Documents both cutaneous viral outcomes together, and their onset in early childhood.
quote_role: PRIMARY_RESULT
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood
counts of CD4+ and CD8+ memory T cells and CD4+ TREGs.
explanation: >-
Confirms recalcitrant warts at cohort scale and identifies them as the feature shared with CD28
deficiency.
quote_role: PRIMARY_RESULT
downstream:
- target: Recalcitrant Cutaneous Warts
causal_link_type: DIRECT
description: Papillomavirus outcome of the failed cutaneous control.
- target: Persistent Molluscum Contagiosum
causal_link_type: DIRECT
description: Poxvirus outcome of the same failure.
mechanism_confidence: ESTABLISHED
- name: Uncontrolled EBV Infection of Smooth Muscle
description: >-
EBV-positive smooth-muscle tumors arise in the setting of impaired immune surveillance. Deficient
EBV-responsive T-cell expansion is demonstrable, but the precise link between individual immune defects
and smooth-muscle infection or tumor growth remains unresolved.
role: consequence
biological_scale: TISSUE
cell_types:
- preferred_term: smooth muscle cell
term:
id: CL:0000192
label: smooth muscle cell
evidence:
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we show four human patients with EBV+ disseminated smooth muscle tumours that carry two homozygous
loss-of-function mutations in the CARMIL2 (RLTPR) gene encoding the capping protein regulator and
myosin 1 linker 2.
explanation: >-
The tumours were the presenting feature in the original four patients, which is why they anchor
this node.
quote_role: PRIMARY_RESULT
- reference: PMID:32625199
reference_title: A Novel Pathogenic Variant in CARMIL2 (RLTPR) Causing CARMIL2 Deficiency and EBV-Associated Smooth Muscle Tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CARMIL2 deficiency is a rare combined immunodeficiency (CID) characterized by defective CD28-mediated
T cell co-stimulation, altered cytoskeletal dynamics, and susceptibility to Epstein Barr Virus smooth
muscle tumors (EBV-SMTs).
explanation: >-
States the susceptibility as a defining feature of the disease rather than a single-family observation.
quote_role: PRIMARY_RESULT
downstream:
- target: EBV-Positive Smooth Muscle Tumor
causal_link_type: DIRECT
description: The tumour is the clinical expression of this node.
mechanism_confidence: ESTABLISHED
- name: B Cell Receptor-Proximal NF-kB Signaling Failure
description: >-
Anti-IgM stimulation of patient B cells fails to induce normal p65 phosphorylation and IκBα degradation.
ERK signaling is relatively preserved, and CD40- and PMA-induced NF-kB responses remain intact in
the reported assays. Mouse B cells do not reproduce this selective human defect.
role: mediator
biological_scale: CELLULAR
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
biological_processes:
- preferred_term: B cell receptor signaling pathway
term:
id: GO:0050853
label: B cell receptor signaling pathway
modifier: DECREASED
evidence:
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
This B cell phenotype does not result solely from the T cell deficiency, as the patients' B cells
fail to activate NF-κB upon B cell receptor (BCR) stimulation.
explanation: >-
Both the measurement and the inference this node exists to record: the humoral defect has its own
proximal cause.
quote_role: PRIMARY_RESULT
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Our study suggests that CARMIL2 governs immunological pathways beyond CD28.
explanation: >-
The cohort study's own conclusion, which is the general form of the claim this node instantiates.
quote_role: PRIMARY_RESULT
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: These data show that RLTPR-deficient B cells have a partially defective signaling pathway, at least via NF-κB, but an intact CD40 signaling pathway, at least for the readouts tested.
explanation: The defect is pathway-specific rather than a failure of every B-cell stimulus.
downstream:
- target: Impaired Specific Antibody Production
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The observed immune defect can contribute to this consequence, but the complete cellular and tissue
route is not established.
- target: Reduced Memory B Cell Compartment
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Disrupted signaling and T-cell help are plausible contributors to formation or maintenance of B-cell memory.
mechanism_confidence: ESTABLISHED
- name: Impaired Specific Antibody Production
description: >-
Specific antibody responses, especially to protein vaccines, are weak despite frequently normal total
serum IgG. Both B-cell-intrinsic signaling and deficient T-cell help contribute.
role: consequence
biological_scale: ORGANISM
cell_types:
- preferred_term: memory B cell
term:
id: CL:0000787
label: memory B cell
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody
responses are weak.
explanation: >-
Establishes the humoral deficit and marks it as one of the features that separates CARMIL2 from
CD28 deficiency.
quote_role: PRIMARY_RESULT
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The patients also display few memory B cells and poor antibody responses.
explanation: The original description of the same deficit.
quote_role: PRIMARY_RESULT
- reference: PMID:32625199
reference_title: A Novel Pathogenic Variant in CARMIL2 (RLTPR) Causing CARMIL2 Deficiency and EBV-Associated Smooth Muscle Tumors.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Defects in both T and B cell compartments were observed, including absent central memory CD8+ T
cells, and decreased frequencies of total and class-switched memory B cells.
explanation: >-
Adds the class-switched memory B cell subset to the general memory B cell deficit.
quote_role: PRIMARY_RESULT
downstream:
- target: Impaired Specific Antibody Response
causal_link_type: DIRECT
description: The measurable clinical expression of this node.
- target: Reduced IgG
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The humoral defect is variably expressed in serum and memory-cell readouts.
mechanism_confidence: ESTABLISHED
- name: Perturbed T Cell Cytoskeletal Organization
description: >-
Patient T-cell assays showed disorganized microtubules and leading-edge actin, increased spontaneous
velocity but reduced directional migration and CXCL12 chemotaxis. Total F-actin and CXCR4 were preserved.
A later, denser collagen assay found normal cellular morphology; it did not measure or refute every
earlier migration endpoint. The contribution to clinical disease remains uncertain.
role: mediator
biological_scale: CELLULAR
cell_types:
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
biological_processes:
- preferred_term: actin cytoskeleton organization
term:
id: GO:0030036
label: actin cytoskeleton organization
modifier: ABNORMAL
evidence:
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Our studies in CARMIL2-deficient T lymphoblasts showed impaired actin distribution in the leading edge and a severely disturbed microtubule network associated with increased spontaneous migratory speed but decreased directness and chemokine-directed migration.
explanation: Direct patient-cell assays document multiple cytoskeletal and migration endpoints.
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix.
explanation: Normal morphology in high-density collagen limits generalization.
mechanism_confidence: ESTABLISHED
- name: Mucocutaneous and Intestinal Immune Dysregulation
description: >-
Reduced regulatory-cell activity and broader immune dysfunction contribute to inflammatory skin and
intestinal disease. Clinical improvement after immune reconstitution supports an immune contribution.
Epithelial-intrinsic effects and the tissue mechanism of gastrointestinal stenosis remain unresolved;
fibrosis has not been demonstrated.
role: consequence
biological_scale: ORGANISM
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory
bowel disease.
explanation: >-
Names mucocutaneous inflammation and inflammatory bowel disease as defining manifestations at cohort
scale.
quote_role: PRIMARY_RESULT
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
IBD was the most severe clinical manifestation, leading to growth retardation, requiring multiple
interventional treatments.
explanation: >-
Establishes the clinical weight of the intestinal arm relative to the rest of the phenotype.
quote_role: PRIMARY_RESULT
downstream:
- target: Atopic Dermatitis
causal_link_type: DIRECT
description: The cutaneous expression of this node.
- target: Inflammatory Bowel Disease
causal_link_type: DIRECT
description: The intestinal expression of this node.
- target: Failure to Thrive
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Intestinal inflammation and chronic diarrhea contribute to poor growth through nutritional and inflammatory
burdens.
- target: Chronic Diarrhea
causal_link_type: DIRECT
description: >-
Chronic diarrhoea is the symptomatic expression of the intestinal inflammation, and is the intermediate
this node's failure-to-thrive edge already names.
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%), recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%), and EBV-related leiomyoma (n = 2, 13%).
explanation: Reports chronic diarrhoea in the CARMIL2 patient cohort.
quote_role: PRIMARY_RESULT
- target: Psoriasiform Dermatitis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.
- target: Seborrheic Dermatitis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.
- target: Eosinophilic Enteropathy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.
- target: Esophageal Stenosis
causal_link_type: UNKNOWN
description: Chronic inflammation is a proposed contributor; tissue fibrosis and the specific mechanism of narrowing have not been demonstrated.
- target: Pyloric Stenosis
causal_link_type: UNKNOWN
description: Chronic inflammation is a proposed contributor; tissue fibrosis and the specific mechanism of narrowing have not been demonstrated.
- target: Duodenal Stenosis
causal_link_type: UNKNOWN
description: Chronic inflammation is a proposed contributor; tissue fibrosis and the specific mechanism of narrowing have not been demonstrated.
- target: Food Allergy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.
- target: Asthma
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.
- target: Rhinitis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.
- target: Eosinophilia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.
- target: Elevated IgE
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Clinical association with immune dysregulation; tissue-specific intermediate mechanisms are incompletely established.
- target: Membranous Nephropathy
causal_link_type: UNKNOWN
description: An immune-mediated contribution is proposed in a single case; causation and the relevant cellular route remain uncertain.
- target: Autoimmune Hemolytic Anemia
causal_link_type: UNKNOWN
description: An immune-mediated contribution is proposed in a single case; causation and the relevant cellular route remain uncertain.
mechanism_confidence: ESTABLISHED
- name: Reduced T Cell Interleukin-2 Production
description: CD28-dependent induction of IL-2 is impaired. This reduces a key growth signal, although cytokine output varies with stimulus and time point.
biological_scale: CELLULAR
evidence:
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: In contrast, TNF and IL-2 productions were not enhanced by CD28 costimulation in patients’ memory CD4+ T cells, although all memory CD4+ T cell express CD28 (Fig.
explanation: CD28 failed to augment IL-2 production in patient memory CD4 T cells.
biological_processes:
- preferred_term: interleukin-2 production
term:
id: GO:0032623
label: interleukin-2 production
downstream:
- target: Reduced Stimulated T Cell Proliferation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Deficient growth-factor output contributes to impaired proliferation; IL-2 rescue supports this route.
mechanism_confidence: ESTABLISHED
- name: Reduced Stimulated T Cell Proliferation
description: Patient T-cell proliferation is reduced with CD3/CD28 costimulation. Additional IL-2 can restore proliferation in some assays, whereas CD25 induction may remain subnormal.
biological_scale: CELLULAR
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: The addition of IL-2 to PBMCs cultures incubated with anti-CD3/CD28 mAb resulted in levels of CD4+ and CD8+ T cell proliferation similar to those observed in HD cell cultures or sorted naive T cells (Fig.
explanation: Proliferation is a rescuable cellular readout, not proof of clinical treatment efficacy.
biological_processes:
- preferred_term: T cell proliferation
term:
id: GO:0042098
label: T cell proliferation
mechanism_confidence: ESTABLISHED
downstream:
- target: Impaired CD3/CD28-Induced T Cell Proliferation
causal_link_type: DIRECT
description: The culture proliferation assay is the measurable phenotype of this cellular defect.
- name: Altered Activated T Cell Survival Program
description: Activated patient CD4 T cells show reduced induction of prosurvival BCL2L1 and increased BCL2L11 in memory cells. Impaired survival is a proposed explanation for reduced cell accumulation; direct apoptosis quantification was not established by these transcript measurements.
biological_scale: CELLULAR
evidence:
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Whereas no significant difference of BCL2 expression was detected in both naive and memory RLTPR-deficient CD4+ T cells, we found significantly lower induction of BCL2L1 in RLTPR-deficient naive (fivefold reduced) and memory (twofold reduced) CD4+ T cells and increased (fourfold) expression of BCL2L11 in RLTPR-deficient memory CD4+ T cells compared with controls (Fig. 6 f).
explanation: The survival-program interpretation is based on expression of apoptosis regulators.
downstream:
- target: Reduced Th1 Effector Output
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Impaired persistence is a proposed contributor; transcript measurements do not establish the entire causal sequence.
- target: Reduced Th17 Effector Output
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Impaired persistence is a proposed contributor; transcript measurements do not establish the entire causal sequence.
- target: Memory T Cell Deficit
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Impaired persistence is a proposed contributor; transcript measurements do not establish the entire causal sequence.
mechanism_confidence: PROVISIONAL
- name: Reduced Th1 Effector Output
description: Accumulated IFN-gamma and other Th1 cytokine outputs are reduced in patient cultures. Preserved TBX21 induction and cytokine-positive fractions among viable cells argue against an absolute inability to specify the Th1 lineage.
biological_scale: CELLULAR
evidence:
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: RLTPR-deficient memory CD4+ T cells exhibited dramatic reductions in production of IFN-γ, TNF, IL-17A/F, and IL-22 (Fig. 6 g), as well as IL-6 and IL-10 (Fig. 6 h).
explanation: Reduced cytokine accumulation is the direct readout.
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Surprisingly, induction of TBX21 and RORC expression in RLTPR-deficient naive CD4+ T cells was comparable with that observed for control naive CD4+ T cells.
explanation: Lineage transcription-factor induction was preserved.
downstream:
- target: Failure of Cell-Mediated Control of Chronic Viral and Fungal Infection
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Reduced effector capacity plausibly contributes to susceptibility, with pathogen-specific contributions unresolved.
mechanism_confidence: ESTABLISHED
- name: Reduced Th17 Effector Output
description: IL-17A/F and IL-22 output is reduced under several stimulation conditions. RORC induction and viable cytokine-positive fractions can be preserved, so survival and activation defects may underlie the output deficit. Later metabolic rescue increased IL17A RNA without a significant increase in secreted IL-17.
biological_scale: CELLULAR
evidence:
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Consistent with this interpretation, analysis of the proportion of viable RLTPR-deficient CD4+ T cells expressing Th1 and Th17 cytokines, as determined by intracellular staining, was similar to controls (not depicted), suggesting the reduction in levels of accumulated secreted cytokines during the culture period is caused by impaired cell survival rather than differentiation.
explanation: Viable-cell analysis argues for a survival contribution rather than a universal differentiation block.
downstream:
- target: Failure of Cell-Mediated Control of Chronic Viral and Fungal Infection
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Reduced effector capacity plausibly contributes to susceptibility, with pathogen-specific contributions unresolved.
mechanism_confidence: ESTABLISHED
- name: Impaired T Follicular Helper Cell Support
description: Circulating Tfh cells are reduced, and activated naive patient T cells show reduced ICOS and CD40L expression. These findings support deficient T-cell help as one contributor to impaired humoral immunity.
biological_scale: CELLULAR
evidence:
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Frequency of CD40L and MFI of ICOS on RLTPR-deficient naive CD4+ T cells were reduced, equating to ∼50% of the levels detected on cells from healthy controls.
explanation: ICOS and CD40L were approximately half of control levels.
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: All tested patients in our cohort had low Treg and cTFH cells, impaired proliferation in response to anti-CD28, and low production of IL-2, IL-17, and IL-21 cytokines after CD28 crosslinking.
explanation: Patient immunophenotyping identifies reduced circulating Tfh cells.
downstream:
- target: Impaired Specific Antibody Production
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Reduced T-cell help can compromise antigen-specific B-cell memory and antibody responses.
- target: Reduced Memory B Cell Compartment
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Disrupted signaling and T-cell help are plausible contributors to formation or maintenance of B-cell memory.
mechanism_confidence: ESTABLISHED
- name: Reduced Natural Killer Cell Degranulation
description: Patient NK cells showed reduced K562-induced degranulation and NKG2D expression; IL-2 prestimulation abolished the measured differences. Functional impairment is distinct from variable NK lymphopenia.
biological_scale: CELLULAR
evidence:
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: NK-cell degranulation in response to co-incubation with the erythroleukemic cell line K562 was impaired and accompanied by a decreased expression of NKG2D.
explanation: K562-induced NK degranulation was reduced.
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: NK cell and CD8 T-cell pre-culturing with IL-2 abrogated the observed differences in degranulation and NKG2D expression (Fig. 6).
explanation: The functional readouts improved after IL-2 pretreatment.
biological_processes:
- preferred_term: natural killer cell degranulation
term:
id: GO:0043320
label: natural killer cell degranulation
downstream:
- target: Failure of Cell-Mediated Control of Chronic Viral and Fungal Infection
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Reduced effector capacity plausibly contributes to susceptibility, with pathogen-specific contributions unresolved.
mechanism_confidence: ESTABLISHED
- name: Reduced Activated T Cell ASCT2 Abundance
description: Activated patient CD4 T cells have reduced surface abundance of the glutamine transporter ASCT2. Transporter expression is measured; reduced glutamine uptake is inferred rather than directly quantified.
biological_scale: MOLECULAR
evidence:
- reference: url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf
reference_title: "https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf"
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Reduced expr ession of ASCT2, the major glutamine trans - porter in T cells, was further confirmed by flo w cytometry
explanation: Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. Flow cytometry confirmed lower surface ASCT2 in activated patient T cells.
downstream:
- target: Impaired Activation-Induced T Cell Metabolic Reprogramming
causal_link_type: UNKNOWN
description: Reduced transporter availability is a candidate contributor, but uptake and metabolic flux were not directly established.
mechanism_confidence: ESTABLISHED
- name: Impaired Activation-Induced T Cell Metabolic Reprogramming
description: Activated patient CD4 T cells show altered transcript and metabolite profiles involving glycolysis, amino-acid metabolism and related pathways. These measurements establish altered abundance, not direct pathway flux or systemic glutamine deficiency.
biological_scale: CELLULAR
evidence:
- reference: PMID:40738287
reference_title: CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: RNA sequencing of CD4+ T cells revealed decreased expression of genes associated with metabolic activity, including mTOR signaling, glycolysis, 1-carbon metabolism, and glutamine metabolism.
explanation: Activated patient CD4 T cells have altered metabolic transcript abundance.
- reference: PMID:40738287
reference_title: CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Whole-cell metabolomics reinforced these results and highlighted glutamine deficiency as a potential driver of the observed metabolic phenotype.
explanation: Metabolite abundance supports the phenotype without establishing flux.
downstream:
- target: Reduced Activated T Cell mTOR Signaling
causal_link_type: UNKNOWN
description: Metabolic supplementation rescues signaling, consistent with coupling; directionality and feedback remain incompletely resolved.
mechanism_confidence: ESTABLISHED
- name: Reduced Activated T Cell mTOR Signaling
description: Reduced phosphorylation of ribosomal protein S6 indicates impaired mTOR-pathway activation in stimulated patient CD4 T cells. Glutamine supplementation improved this readout in culture.
biological_scale: MOLECULAR
evidence:
- reference: PMID:40738287
reference_title: CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Glutamine supplementation restored NF-κB and mTOR activity, as measured by p-65 and RPS6 phosphorylation, respectively, and upregulated the expression of IL17A in CARMIL2-mutated CD4+ T cells.
explanation: RPS6 phosphorylation is the reported mTOR readout.
biological_processes:
- preferred_term: TORC1 signaling
term:
id: GO:0038202
label: TORC1 signaling
mechanism_confidence: ESTABLISHED
- name: Reduced Memory B Cell Compartment
description: Circulating memory B cells, including class-switched cells, are reduced in many patients. The relative contributions of B-cell-intrinsic signaling and impaired T-cell help remain uncertain.
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Similarly, B cell counts were low in only one patient (P2), but nine (60%) had low percentages of class-switched memory B cells concomitant with elevated naïve B cells.
explanation: The longitudinal cohort quantifies class-switched memory deficiency.
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak.
explanation: The larger cohort confirms the memory B-cell deficit.
downstream:
- target: Decreased Memory B Cell Proportion
causal_link_type: DIRECT
description: >-
Low circulating memory B cell counts are the cellular counterpart of the impaired humoral memory,
and one of the two features that separate CARMIL2 deficiency from CD28 deficiency.
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak.
explanation: Reports the low memory B cell counts distinguishing CARMIL2 from CD28 deficiency.
quote_role: PRIMARY_RESULT
- target: Decreased Class-Switched Memory B Cells
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The humoral defect is variably expressed in serum and memory-cell readouts.
phenotypes:
- name: Recalcitrant Cutaneous Warts
description: >-
Warts occurred in 7/15 patients (47%) in a longitudinal cohort. Some were limited or self-limiting,
whereas others persisted or became extensive; onset need not be in infancy.
category: Dermatological
phenotype_term:
preferred_term: Recalcitrant cutaneous warts
term:
id: HP:0200043
label: Verrucae
temporality: CHRONIC
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: HPV was the most common cutaneous infection (n=7, 47%, P3, P4, P6, P7, P11, P14, P15).
explanation: Seven of 15 had cutaneous HPV disease.
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Some patients had very persistent and widespread warts (P3 and P4, Fig. 1D), while others had only a few and self-limiting warts (P6, P7, P11, P14, P15).
explanation: The cohort included both persistent and self-limited warts.
frequency: FREQUENT
- name: Persistent Molluscum Contagiosum
description: >-
Molluscum contagiosum occurred in 3/15 patients (20%) in a longitudinal cohort and can be persistent
or extensive.
category: Dermatological
phenotype_term:
preferred_term: Persistent molluscum contagiosum
term:
id: HP:0032163
label: Unusual molluscum contagiosum
temporality: CHRONIC
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Another common viral skin infection was molluscum contagiosum (n=3, 20%, Table 1).
explanation: Molluscum contagiosum occurred in 3/15 patients (20%) in a longitudinal cohort and can be persistent or extensive.
frequency: OCCASIONAL
- name: Recurrent Mucocutaneous Candidiasis
description: >-
Chronic mucocutaneous candidiasis affected 24/87 (28%) in the large cohort, including oral, intertriginous,
nail or esophageal disease.
category: Infectious
phenotype_term:
preferred_term: Mucocutaneous candidiasis
term:
id: HP:0002728
label: Chronic mucocutaneous candidiasis
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Bacterial skin abscesses occurred in 26/87 (30%), and chronic mucocutaneous candidiasis, presenting as oral thrush, intertrigo, onychomycosis, and/or esophagitis, occurred in 24/87 (28%) CARMIL2-deficient individuals.
explanation: Chronic mucocutaneous candidiasis affected 24/87 (28%) in the large cohort, including oral, intertriginous, nail or esophageal disease.
frequency: OCCASIONAL
- name: Recurrent Infections
description: >-
A broad infection burden spanning bacterial, mycobacterial, viral and fungal pathogens, including
invasive tuberculosis in the original series.
category: Infectious
frequency: FREQUENT
phenotype_term:
preferred_term: Recurrent infections
term:
id: HP:0002719
label: Recurrent infections
temporality: RECURRENT
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%),
recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%),
and EBV-related leiomyoma (n = 2, 13%).
explanation: >-
Reports recurrent infections in 10 of 15 patients (67 per cent), which is the `FREQUENT` band.
quote_role: PRIMARY_RESULT
- name: EBV-Positive Smooth Muscle Tumor
description: >-
EBV-positive smooth muscle tumors affected 15/87 (17%) clinically characterized patients and can be
multifocal. EBV DNA was undetectable in blood in 3/15 tumor cases; a negative blood test does not
exclude a tumor.
category: Neoplastic
phenotype_term:
preferred_term: Epstein-Barr virus-positive smooth muscle tumor
term:
id: HP:0031459
label: Soft tissue neoplasm
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: EBV+ SMTs were reported in 15/87 (17%) CARMIL2-deficient individuals.
explanation: EBV-positive smooth muscle tumors affected 15/87 (17%) clinically characterized patients and can be multifocal. EBV DNA was undetectable in blood in 3/15 tumor cases; a negative blood test does not exclude a tumor.
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: EBV viremia was not detected in 3/15 affected individuals (20%) and an absence of viremia should not, therefore, be regarded as an exclusion criterion for EBV+ SMTs (Magg et al., 2018).
explanation: Blood viral testing can be negative despite tissue-associated tumors.
frequency: OCCASIONAL
- name: Atopic Dermatitis
description: >-
Atopic dermatitis occurred in 60/87 (69%) in the large cohort. Psoriasiform and seborrheic disease
are recorded separately.
category: Dermatological
phenotype_term:
preferred_term: Atopic dermatitis
term:
id: HP:0001047
label: Atopic dermatitis
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Atopic dermatitis affected 60/87 (69%) CARMIL2-deficient individuals within the first 2 yr of life (Fig. 7 F).
explanation: Atopic dermatitis occurred in 60/87 (69%) in the large cohort. Psoriasiform and seborrheic disease are recorded separately.
frequency: FREQUENT
- name: Inflammatory Bowel Disease
description: >-
Histologically confirmed inflammatory bowel disease occurred in 19/87 (22%); onset was often before
age 6 but can be later. Severe colitis may resist medical treatment.
category: Gastrointestinal
phenotype_term:
preferred_term: Inflammatory colitis
term:
id: HP:0002583
label: Colitis
temporality: CHRONIC
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: GI manifestations were reported in 55/87 (63%) CARMIL2-deficient individuals, of whom 19/87 (22%) had histologically confirmed inflammatory bowel disease (IBD).
explanation: Histologically confirmed inflammatory bowel disease occurred in 19/87 (22%); onset was often before age 6 but can be later. Severe colitis may resist medical treatment.
frequency: OCCASIONAL
- name: Chronic Diarrhea
description: >-
Chronic diarrhea occurred in 4/15 (27%) in the longitudinal cohort and may accompany intestinal inflammation
or infection.
category: Gastrointestinal
frequency: OCCASIONAL
phenotype_term:
preferred_term: Chronic diarrhea
term:
id: HP:0002028
label: Chronic diarrhea
temporality: CHRONIC
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%),
recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%),
and EBV-related leiomyoma (n = 2, 13%).
explanation: >-
Chronic diarrhoea in 4 of 15 patients (27 per cent) is the `OCCASIONAL` band.
quote_role: PRIMARY_RESULT
- name: Failure to Thrive
description: >-
Growth faltering affected 46/84 (55%) and was associated with gastrointestinal involvement; infection
and other nutritional burdens can also contribute.
category: Growth
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Failure to thrive was noted in 46/84 (55%) CARMIL2-deficient individuals and was positively associated with GI tract involvement (r = 0.31, P < 0.01).
explanation: Growth faltering affected 46/84 (55%) and was associated with gastrointestinal involvement; infection and other nutritional burdens can also contribute.
frequency: FREQUENT
- name: Decreased Regulatory T Cell Proportion
description: >-
Circulating regulatory T cells are markedly reduced or absent, and CD25 expression within the residual
compartment is itself low.
category: Immunological
phenotype_term:
preferred_term: Decreased regulatory T cell proportion
term:
id: HP:0020113
label: Decreased regulatory T cell proportion
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood
counts of CD4+ and CD8+ memory T cells and CD4+ TREGs.
explanation: Reports the low Treg counts at cohort scale.
quote_role: PRIMARY_RESULT
- name: Decreased Memory T Cell Proportion
description: >-
CD4+ and CD8+ memory T cell counts are low, with a reciprocal skew of the CD4+ compartment toward
naive cells.
category: Immunological
phenotype_term:
preferred_term: Decreased memory T cell proportion
term:
id: HP:0032183
label: Decreased memory T cell proportion
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood
counts of CD4+ and CD8+ memory T cells and CD4+ TREGs.
explanation: Reports the low memory T cell counts at cohort scale.
quote_role: PRIMARY_RESULT
- name: Decreased Memory B Cell Proportion
description: >-
Memory B cells, including the class-switched subset, are reduced. This is one of the two laboratory
features that distinguish CARMIL2 from CD28 deficiency.
category: Immunological
phenotype_term:
preferred_term: Decreased memory B cell proportion
term:
id: HP:0030374
label: Decreased memory B cell proportion
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody
responses are weak.
explanation: >-
Reports the memory B cell deficit and marks it as discriminating against CD28 deficiency.
quote_role: PRIMARY_RESULT
- name: Reduced Natural Killer Cell Count
description: >-
Reduced NK counts were frequent in later cohorts, including 13/15 in the longitudinal series, but
normal counts were reported in the initial six-patient series; NK lymphopenia is not obligatory.
category: Immunological
phenotype_term:
preferred_term: Reduced natural killer cell count
term:
id: HP:0040218
label: Reduced total natural killer cell count
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak.
explanation: Reduced NK counts were frequent in later cohorts, including 13/15 in the longitudinal series, but normal counts were reported in the initial six-patient series; NK lymphopenia is not obligatory.
- name: Impaired Specific Antibody Response
description: >-
Responses to protein vaccines can be poor despite normal serum IgG: low or absent tetanus antibodies
occurred in 23/32 (72%), and diphtheria antibodies in 15/15 tested patients. These denominators describe
tested subgroups.
category: Immunological
phenotype_term:
preferred_term: Impaired specific antibody response
term:
id: HP:0012475
label: Impaired specific antibody response
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Despite generally normal Ig concentrations, CARMIL2-deficient individuals displayed abnormally weak-specific Ab responses to protein-based booster vaccines, as 23/32 (72%) and 15/15 (100%) of the patients had low titers or no Abs against tetanus and diphtheria toxoid, respectively (Fig. 6 B and Table S4).
explanation: 'Responses to protein vaccines can be poor despite normal serum IgG: low or absent tetanus antibodies occurred in 23/32 (72%), and diphtheria antibodies in 15/15 tested patients. These denominators describe tested subgroups.'
frequency: FREQUENT
- name: Impaired CD3/CD28-Induced T Cell Proliferation
description: >-
Reduced proliferation after CD3/CD28 stimulation is a characteristic functional finding even when
total circulating T-cell counts are preserved. Responses depend on the stimulus and cell subset.
category: Immunological
phenotype_term:
preferred_term: Reduced CD3/CD28-stimulated T cell proliferation
term:
id: HP:0031402
label: Decreased antigen-specific T cell proliferation
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: These results confirm that CARMIL2 deficiency results in markedly impaired CD28 cosignaling, leading to lower T cell proliferation capacities, as observed in individuals with CD28 deficiency (Béziat et al., 2021), and that these phenotypes can be rescued by the addition of IL-2, at least in vitro.
explanation: Reduced proliferation after CD3/CD28 stimulation is a characteristic functional finding even when total circulating T-cell counts are preserved. Responses depend on the stimulus and cell subset.
- name: Psoriasiform Dermatitis
description: Psoriasis-like lesions occurred in 33/87 patients (38%) and are distinct from the atopic dermatitis count.
category: Dermatological
phenotype_term:
preferred_term: Psoriasiform Dermatitis
term:
id: HP:0003765
label: Psoriasiform dermatitis
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: In addition, psoriasis-like lesions were noted in 33/87 (38%) individuals.
explanation: Psoriasis-like lesions occurred in 33/87 patients (38%) and are distinct from the atopic dermatitis count.
frequency: FREQUENT
- name: Seborrheic Dermatitis
description: Seborrheic scalp disease is reported in the Norwegian founder kindreds; a population frequency is not established.
category: Dermatological
phenotype_term:
preferred_term: Seborrheic Dermatitis
term:
id: HP:0001051
label: Seborrheic dermatitis
evidence:
- reference: PMID:27896283
reference_title: A potential founder variant in CARMIL2/RLTPR in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: The patient has a variable degree of psoriatic lesions and seborrheic dermatitis, mainly affecting the scalp, and recurrent bacterial skin infections, occurring in the dermatitis lesions.
explanation: Seborrheic scalp disease is reported in the Norwegian founder kindreds; a population frequency is not established.
- name: Recurrent Upper Respiratory Tract Infections
description: Recurrent upper respiratory infections occurred in 53/87 (61%).
category: Infectious
phenotype_term:
preferred_term: Recurrent Upper Respiratory Tract Infections
term:
id: HP:0002788
label: Recurrent upper respiratory tract infections
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Recurrent upper and lower respiratory tract infections were noted in 53/87 (61%) and 53/87 (61%) CARMIL2-deficient individuals, respectively (Fig. 7 E).
explanation: Recurrent upper respiratory infections occurred in 53/87 (61%).
frequency: FREQUENT
- name: Recurrent Lower Respiratory Tract Infections
description: Recurrent lower respiratory infections occurred in 53/87 (61%).
category: Infectious
phenotype_term:
preferred_term: Recurrent Lower Respiratory Tract Infections
term:
id: HP:0002783
label: Recurrent lower respiratory tract infections
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Recurrent upper and lower respiratory tract infections were noted in 53/87 (61%) and 53/87 (61%) CARMIL2-deficient individuals, respectively (Fig. 7 E).
explanation: Recurrent lower respiratory infections occurred in 53/87 (61%).
frequency: FREQUENT
- name: Bronchiectasis
description: Bronchiectasis occurred in 12/87 (14%) and can complicate recurrent respiratory infection.
category: Respiratory
phenotype_term:
preferred_term: Bronchiectasis
term:
id: HP:0002110
label: Bronchiectasis
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Bronchiectasis was reported in 12/87 (14%) CARMIL2-deficient individuals.
explanation: Bronchiectasis occurred in 12/87 (14%) and can complicate recurrent respiratory infection.
frequency: OCCASIONAL
- name: Bacterial Skin Abscesses
description: Bacterial cutaneous abscesses occurred in 26/87 (30%).
category: Infectious
phenotype_term:
preferred_term: Bacterial Skin Abscesses
term:
id: HP:0031292
label: Cutaneous abscess
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Bacterial skin abscesses occurred in 26/87 (30%), and chronic mucocutaneous candidiasis, presenting as oral thrush, intertrigo, onychomycosis, and/or esophagitis, occurred in 24/87 (28%) CARMIL2-deficient individuals.
explanation: Bacterial cutaneous abscesses occurred in 26/87 (30%).
frequency: FREQUENT
- name: Severe Cytomegalovirus Infection
description: Clinical CMV disease, including retinitis or colitis, occurred in 11/87 (13%); this is distinct from asymptomatic viral replication.
category: Infectious
phenotype_term:
preferred_term: Severe Cytomegalovirus Infection
term:
id: HP:0031692
label: Severe cytomegalovirus infection
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: In addition to CMV pneumonia, five cases of CMV-induced retinitis and four cases of CMV colitis were reported, so clinical CMV disease was observed in 11/87 (13%) CARMIL2-deficient individuals.
explanation: Clinical CMV disease, including retinitis or colitis, occurred in 11/87 (13%); this is distinct from asymptomatic viral replication.
frequency: OCCASIONAL
- name: Eosinophilic Enteropathy
description: Eosinophilic enteropathy affected 21/87 (24%), often as esophagitis.
category: Gastrointestinal
phenotype_term:
preferred_term: Eosinophilic Enteropathy
term:
id: HP:0032064
label: Gastrointestinal eosinophilia
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Eosinophilic enteropathy, usually manifesting as esophagitis, was observed in 21/87 individuals (24%).
explanation: Eosinophilic enteropathy affected 21/87 (24%), often as esophagitis.
frequency: OCCASIONAL
- name: Esophageal Stenosis
description: Esophageal narrowing can cause progressive dysphagia and may require dilation; the tissue mechanism is unresolved.
category: Gastrointestinal
phenotype_term:
preferred_term: Esophageal Stenosis
term:
id: HP:0010450
label: Esophageal stenosis
evidence:
- reference: url:https://all-imm.com/index.php/aei/article/view/1595/2445
reference_title: "Gastrointestinal stenosis: an underrecognized complication of CARMIL2 deficiency | Allergologia et Immunopathologia"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: At 16 years, he developed progressive dysphagia due to esophageal stricture with associated esophagitis and nodular pangastritis, partially relieved by pneumatic dilation.
explanation: Esophageal narrowing can cause progressive dysphagia and may require dilation; the tissue mechanism is unresolved.
- name: Pyloric Stenosis
description: Pyloric obstruction has required surgery in affected children, including two siblings with symptom resolution after repair.
category: Gastrointestinal
phenotype_term:
preferred_term: Pyloric Stenosis
term:
id: HP:0002021
label: Pyloric stenosis
evidence:
- reference: url:https://all-imm.com/index.php/aei/article/view/1595/2445
reference_title: "Gastrointestinal stenosis: an underrecognized complication of CARMIL2 deficiency | Allergologia et Immunopathologia"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Pyloric stenosis occurred at 6 years and was surgically corrected, resulting in complete resolution.
explanation: Pyloric obstruction has required surgery in affected children, including two siblings with symptom resolution after repair.
- name: Duodenal Stenosis
description: Duodenal narrowing is a reported upper gastrointestinal complication. Aggregate stenosis counts are not assigned to each anatomical site.
category: Gastrointestinal
phenotype_term:
preferred_term: Duodenal Stenosis
term:
id: HP:0100867
label: Duodenal stenosis
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: In nine individuals, upper GI tract involvement led to esophageal, pyloric, or duodenal stenosis.
explanation: Duodenal narrowing is a reported upper gastrointestinal complication. Aggregate stenosis counts are not assigned to each anatomical site.
- name: Food Allergy
description: Food allergy was reported in 12/87 (14%).
category: Immunological
phenotype_term:
preferred_term: Food Allergy
term:
id: HP:0500093
label: Food allergy
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Food allergies were reported in 12/87 (14%) and allergic asthma was diagnosed in 33/87 (38%) CARMIL2-deficient individuals.
explanation: Food allergy was reported in 12/87 (14%).
frequency: OCCASIONAL
- name: Asthma
description: Asthma occurred in 33/87 (38%) in the large cohort; another cohort showed that demonstrable allergen sensitization is not universal.
category: Respiratory
phenotype_term:
preferred_term: Asthma
term:
id: HP:0002099
label: Asthma
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Food allergies were reported in 12/87 (14%) and allergic asthma was diagnosed in 33/87 (38%) CARMIL2-deficient individuals.
explanation: Asthma occurred in 33/87 (38%) in the large cohort; another cohort showed that demonstrable allergen sensitization is not universal.
frequency: FREQUENT
- name: Rhinitis
description: Rhinitis with congestion and rhinorrhea occurred in 3/15 (20%) and responded to intranasal corticosteroids.
category: Respiratory
phenotype_term:
preferred_term: Rhinitis
term:
id: HP:0012384
label: Rhinitis
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: P3, P7, and P15 (20% of patients) had rhinitis, with chronic nasal congestion and rhinorrhea, which was sensitive to intranasal corticosteroids.
explanation: Rhinitis with congestion and rhinorrhea occurred in 3/15 (20%) and responded to intranasal corticosteroids.
frequency: OCCASIONAL
- name: Eosinophilia
description: Peripheral eosinophilia was present in 7/15 (47%) at evaluation in the longitudinal cohort.
category: Immunological
phenotype_term:
preferred_term: Eosinophilia
term:
id: HP:0001880
label: Increased total eosinophil count
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: During the time of evaluation, eosinophilia was detected in seven patients (47%).
explanation: Peripheral eosinophilia was present in 7/15 (47%) at evaluation in the longitudinal cohort.
frequency: FREQUENT
- name: Elevated IgE
description: IgE was elevated in 3/15 (20%) in the longitudinal cohort; normal or low concentrations also occur.
category: Immunological
phenotype_term:
preferred_term: Elevated IgE
term:
id: HP:0003212
label: Increased circulating IgE concentration
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: IgE was slightly elevated in three (20%) patients.
explanation: IgE was elevated in 3/15 (20%) in the longitudinal cohort; normal or low concentrations also occur.
frequency: OCCASIONAL
- name: Reduced IgG
description: Reduced serum IgG occurred in 12/80 (15%); normal IgG does not exclude functional antibody deficiency.
category: Immunological
phenotype_term:
preferred_term: Reduced IgG
term:
id: HP:0004315
label: Decreased circulating IgG concentration
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: We analyzed the impact of this defect on B cell function and found that serum IgG concentrations were within the normal range in most CARMIL2-deficient individuals, as only 12/80 (15%) presented hypogammaglobulinemia (Fig. 6 A and Table S4).
explanation: Reduced serum IgG occurred in 12/80 (15%); normal IgG does not exclude functional antibody deficiency.
frequency: OCCASIONAL
- name: Decreased Class-Switched Memory B Cells
description: Class-switched memory B cells were low in 9/15 (60%) in the longitudinal cohort.
category: Immunological
phenotype_term:
preferred_term: Decreased Class-Switched Memory B Cells
term:
id: HP:0030388
label: Decreased class-switched memory B cell proportion
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Similarly, B cell counts were low in only one patient (P2), but nine (60%) had low percentages of class-switched memory B cells concomitant with elevated naïve B cells.
explanation: Class-switched memory B cells were low in 9/15 (60%) in the longitudinal cohort.
frequency: FREQUENT
- name: Reduced CD25 Induction
description: CD25 induction after CD3/CD28 stimulation is reduced and may remain below control levels despite IL-2 supplementation.
category: Immunological
phenotype_term:
preferred_term: Reduced CD25 Induction
term:
id: HP:0031270
label: Decreased CD25 upregulation upon TCR activation
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: CD25 upregulation following anti-CD3/CD28 stimulation of PBMCs was also increased by exogenous IL-2, however it did not reach the levels of healthy control cells (Fig.
explanation: CD25 induction after CD3/CD28 stimulation is reduced and may remain below control levels despite IL-2 supplementation.
- name: Membranous Nephropathy
description: A single child with biallelic CARMIL2 variation had biopsy-confirmed secondary membranous nephropathy and nephrotic syndrome. Its frequency and direct mechanistic relationship to CARMIL2 remain uncertain.
category: Renal
phenotype_term:
preferred_term: Membranous Nephropathy
term:
id: HP:0012578
label: Membranous nephropathy
evidence:
- reference: PMID:39649299
reference_title: Secondary Membranous Nephropathy and Immunodeficiency due to a Novel Biallelic Variant in CARMIL2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Her renal biopsy was suggestive of membranous nephropathy.
explanation: A single child with biallelic CARMIL2 variation had biopsy-confirmed secondary membranous nephropathy and nephrotic syndrome. Its frequency and direct mechanistic relationship to CARMIL2 remain uncertain.
- name: Autoimmune Hemolytic Anemia
description: Coombs-positive hemolytic anemia was described in the same renal case; this rare association does not establish a common autoimmune phenotype.
category: Hematological
phenotype_term:
preferred_term: Autoimmune Hemolytic Anemia
term:
id: HP:0001890
label: Autoimmune hemolytic anemia
evidence:
- reference: PMID:39649299
reference_title: Secondary Membranous Nephropathy and Immunodeficiency due to a Novel Biallelic Variant in CARMIL2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: 'Her laboratory results showed 24-hour urine protein level of 63 mg/m2/h, hypoalbuminemia (serum albumin: 2.9 g/dL (3.5–5 g/dL); severe anemia (hemoglobin 3.8 g/dL (11–15 g/dL)), elevated erythrocyte sedimentation rate (104 mm/h), and a positive directs Coombs test.'
explanation: Coombs-positive hemolytic anemia was described in the same renal case; this rare association does not establish a common autoimmune phenotype.
- reference: PMID:39649299
reference_title: Secondary Membranous Nephropathy and Immunodeficiency due to a Novel Biallelic Variant in CARMIL2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: We hypothesize that a reduced number of Treg cells can lead to the breakdown of immune tolerance leading to the secondary phenotype of membranous nephropathy and autoimmune hemolytic anemia.
explanation: The case authors identify autoimmune hemolytic anemia.
genetic:
- name: CARMIL2
gene_term:
preferred_term: CARMIL2
term:
id: hgnc:27089
label: CARMIL2
relationship_type: CAUSATIVE
notes: >-
CARMIL2 loss of function causes autosomal recessive combined immunodeficiency. The 89-person cohort
contained 49 germline variants across 52 families, including compound heterozygotes. Predominant functional
leukocyte isoform 3 must be distinguished from the previously annotated isoform 1; minor isoform 2
is also functional in complementation assays. A synonymous or missense annotation on one transcript
may conceal a splice defect on the relevant transcript. Somatic reversion in selected T-cell compartments
can lessen disease severity without correcting all immune lineages.
evidence:
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we show four human patients with EBV+ disseminated smooth muscle tumours that carry two homozygous
loss-of-function mutations in the CARMIL2 (RLTPR) gene encoding the capping protein regulator and
myosin 1 linker 2.
explanation: >-
Establishes the causal gene, its product, and the biallelic loss-of-function mechanism.
quote_role: PRIMARY_RESULT
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Transcript 3 was expressed in HD cells, but RT-PCR and Sanger sequencing identified only transcript 1 in P42 T cell blasts, with the retention of 108 nucleotides of intron 14 (Fig. 1 K).
explanation: RNA analysis explains the isoform-dependent splice consequence.
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Two individuals displayed a heterozygous reversion to the WT allele (P53, P57), and P1 had a heterozygous somatic missense variant at the site of the mutation (c.1578C>G, p.Cys526Trp) restoring normal splicing and CD28 signaling (Fig. 8, A and B; and Fig.
explanation: Somatic repair can restore function in selected T-cell lineages.
gene_disease_validity:
- validity_classification: DEFINITIVE
classified_by: CLINGEN
external_id: CGGV:assertion_0055cbc0-64df-4f38-9074-495f4ac74e1c-2024-03-12T160000.000Z
notes: ClinGen Primary Immune Regulatory Disorders Expert Panel classified this autosomal recessive association as Definitive on 12 March 2024.
evidence:
- reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0055cbc0-64df-4f38-9074-495f4ac74e1c-2024-03-12T160000.000Z
reference_title: 'curation results for Gene-Disease Validity'
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: In summary, there is definitive evidence supporting the relationship between ... and autosomal recessive severe combined immunodeficiency due to CARMIL2 deficiency.
explanation: The primary ClinGen curation explicitly assigns definitive evidence.
diagnosis:
- name: Molecular Diagnosis
description: Identify biallelic pathogenic CARMIL2 variants with sequencing and segregation analysis, interpreting splice consequences against the functional leukocyte transcript. Functional studies are useful for uncertain alleles.
diagnosis_term:
preferred_term: Whole Exome Sequencing
term:
id: NCIT:C101295
label: Whole Exome Sequencing
evidence:
- reference: PMID:29479355
reference_title: Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Through the use of whole exome sequencing and autozygome-guided analysis, we uncovered two mutations
not previously reported (p.R50T and p.L846Sfs) in CARMIL2.
explanation: >-
Establishes exome sequencing, with autozygosity mapping in consanguineous families, as the diagnostic
route.
quote_role: PRIMARY_RESULT
- name: Immune Phenotyping and Functional Confirmation
description: Measure memory T cells, Tregs, memory B cells, NK cells, immunoglobulins and vaccine-specific antibodies. CARMIL2 protein expression and stimulated T-cell proliferation or NF-kB assays can establish functional impairment; normal total counts or IgG do not exclude disease.
diagnosis_term:
preferred_term: Flow Cytometry
term:
id: NCIT:C16585
label: Flow Cytometry
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: We analyzed the impact of this defect on B cell function and found that serum IgG concentrations were within the normal range in most CARMIL2-deficient individuals, as only 12/80 (15%) presented hypogammaglobulinemia (Fig. 6 A and Table S4).
explanation: Most patients had normal serum IgG despite immune dysfunction.
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Despite generally normal Ig concentrations, CARMIL2-deficient individuals displayed abnormally weak-specific Ab responses to protein-based booster vaccines, as 23/32 (72%) and 15/15 (100%) of the patients had low titers or no Abs against tetanus and diphtheria toxoid, respectively (Fig. 6 B and Table S4).
explanation: Specific vaccine responses reveal defects missed by routine immunoglobulin quantification.
- reference: PMID:31115454
reference_title: CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation,
consistent with CARMIL2 deficiency.
explanation: >-
Establishes the functional confirmation step that follows the genetic finding.
quote_role: PRIMARY_RESULT
- name: Consider CARMIL2 Deficiency in Very Early Onset Inflammatory Bowel Disease
description: >-
Children presenting with very early onset inflammatory bowel disease should be evaluated for an underlying
inborn error of immunity, because the immunological diagnosis changes management. CARMIL2 deficiency
is one of the monogenic causes reached this way, and the intestinal disease may precede recognition
of the immunodeficiency.
evidence:
- reference: PMID:31115454
reference_title: CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This example illustrates that early diagnosis of underlying PID is crucial for the treatment and
prognosis of children with VEO-IBD.
explanation: >-
States the diagnostic recommendation this entry records, in the setting where CARMIL2 deficiency
is most likely to be missed.
quote_role: PRIMARY_RESULT
- name: Screening for EBV-Positive Smooth Muscle Tumors
description: The large cohort recommends whole-body imaging, ideally MRI, to screen for EBV-positive smooth muscle tumors. Blood EBV testing cannot exclude tumors. Tissue evaluation with smooth-muscle markers and EBER establishes tumor association; this recommendation is based on observational evidence.
diagnosis_term:
preferred_term: Magnetic Resonance Imaging
term:
id: NCIT:C16809
label: Magnetic Resonance Imaging
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: It therefore appears important to screen CARMIL2-deficient individuals for the presence of EBV+ SMTs by whole-body imaging techniques, ideally full-body magnetic resonance imaging, because blood tests are unable to detect these tumors.
explanation: The primary cohort proposes whole-body MRI because blood testing can miss tumors.
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: EBV viremia was not detected in 3/15 affected individuals (20%) and an absence of viremia should not, therefore, be regarded as an exclusion criterion for EBV+ SMTs (Magg et al., 2018).
explanation: Negative viremia is not an exclusion criterion.
- name: Assessment of Progressive Gastrointestinal Symptoms
description: Persistent vomiting, gastric stasis or dysphagia warrants assessment for structural narrowing using endoscopy and appropriate imaging. Biopsy distinguishes inflammation, eosinophilic involvement and infection; stenosis does not by itself establish fibrosis.
diagnosis_term:
preferred_term: Gastrointestinal Endoscopy
term:
id: NCIT:C78162
label: Gastrointestinal Endoscopy
evidence:
- reference: url:https://all-imm.com/index.php/aei/article/view/1595/2445
reference_title: "Gastrointestinal stenosis: an underrecognized complication of CARMIL2 deficiency | Allergologia et Immunopathologia"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: At 16 years, he developed progressive dysphagia due to esophageal stricture with associated esophagitis and nodular pangastritis, partially relieved by pneumatic dilation.
explanation: Endoscopy and clinical assessment identified a treatable esophageal narrowing.
- reference: url:https://all-imm.com/index.php/aei/article/view/1595/2445
reference_title: "Gastrointestinal stenosis: an underrecognized complication of CARMIL2 deficiency | Allergologia et Immunopathologia"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Histopathological confirmation of fibrosis is not available, and imaging findings are nonspecific and do not permit direct assessment of fibrotic changes.
explanation: The report expressly limits mechanistic interpretation of the stenosis.
treatments:
- name: Allogeneic Hematopoietic Cell Transplantation
description: A retrospective series of 17 patients receiving 19 transplants reported 82.4% survival at a median follow-up of 37 months and 61.8% event-free survival. Immune and inflammatory manifestations improved in survivors, but three patients died early and two required repeat HCT for graft failure. Among five patients with EBV-positive tumors, one had complete remission, two partial remission, one stable disease and one progression. Residual immune defects occurred with mixed chimerism. These data support early specialist transplant assessment, while benefit and risk remain individualized.
therapeutic_modality: CELL_THERAPY
treatment_term:
preferred_term: Allogeneic Hematopoietic Cell Transplantation
term:
id: NCIT:C46089
label: Allogeneic Hematopoietic Stem Cell Transplantation
evidence:
- reference: PMID:42529607
reference_title: Allogeneic hematopoietic cell transplantation is curative in CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Three patients died during the early posttransplant period (overall survival, 82.4%), and two required a second HCT for graft failure.
explanation: The series reports both survival and transplant failures.
- reference: PMID:42529607
reference_title: Allogeneic hematopoietic cell transplantation is curative in CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: After HCT, one patient achieved complete remission (P13, 20%), two showed a partial remission (P5 and P7, 40%), one had stable disease (P8, 20%), and one suffered from progressive disease (P1, 20%), contributing to an early multifactorial respiratory failure and subsequent death 1 mo after HCT.
explanation: Tumor responses were variable, not universal cure.
- reference: PMID:42529607
reference_title: Allogeneic hematopoietic cell transplantation is curative in CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Overall event-free survival (EFS) was 61.8% (Fig. 1 A), with events defined as death of any cause or graft failure.
explanation: Event-free survival accounts for death or graft failure.
- reference: PMID:42529607
reference_title: Allogeneic hematopoietic cell transplantation is curative in CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Still, our data indicate proper immune reconstitution in patients exhibiting full donor chimerism, whereas P9, with mixed chimerism, shows reduced counts of Treg and CD4+ memory T cells and an impaired T cell proliferation upon CD28 co-stimulation after HCT.
explanation: Full versus mixed donor chimerism had different immune readouts.
target_mechanisms:
- target: Reduced Functional CARMIL2 Protein
description: Donor hematopoiesis supplies cells with functional CARMIL2; it does not repair the recipient germline genotype or guarantee complete immune reconstitution.
evidence:
- reference: PMID:42529607
reference_title: Allogeneic hematopoietic cell transplantation is curative in CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Three patients died during the early posttransplant period (overall survival, 82.4%), and two required a second HCT for graft failure.
explanation: The series reports both survival and transplant failures.
- reference: PMID:42529607
reference_title: Allogeneic hematopoietic cell transplantation is curative in CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: After HCT, one patient achieved complete remission (P13, 20%), two showed a partial remission (P5 and P7, 40%), one had stable disease (P8, 20%), and one suffered from progressive disease (P1, 20%), contributing to an early multifactorial respiratory failure and subsequent death 1 mo after HCT.
explanation: Tumor responses were variable, not universal cure.
- reference: PMID:42529607
reference_title: Allogeneic hematopoietic cell transplantation is curative in CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Overall event-free survival (EFS) was 61.8% (Fig. 1 A), with events defined as death of any cause or graft failure.
explanation: Event-free survival accounts for death or graft failure.
- name: Immunoglobulin Replacement Therapy
description: Immunoglobulin replacement was given to 7/15 patients in a longitudinal cohort because of infections and impaired antibody responses, even when total IgG was not low. Combined prophylaxis and replacement reduced infection frequency observationally. After HCT, no patient in the transplant cohort required replacement beyond 24 months; earlier post-transplant support may still be needed.
therapeutic_modality: PROTEIN_REPLACEMENT
treatment_term:
preferred_term: Immunoglobulin Replacement Therapy
term:
id: NCIT:C62710
label: Immunoglobulin Therapy
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Because of recurrent infections and dysgammaglobulinemia with poor antibody responses, five patients (33%, P3, P4, P6, P7, P15) received prophylactic antibiotics and seven patients (47%, P3, P6, P7, P9–11, P15) were commenced on immunoglobulin replacement therapy (IgRT) with one receiving via subcutaneous and six via intravenous routes.
explanation: The primary cohort directly documents intravenous and subcutaneous replacement.
- reference: PMID:42529607
reference_title: Allogeneic hematopoietic cell transplantation is curative in CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Similarly, CD19+ B cell deficiency (<200/μl) was reported only in P14 (+26 mo), and no patient required immunoglobulin replacement therapy (IGRT) beyond 24 mo after HCT.
explanation: The full results specify the post-transplant timing.
target_mechanisms:
- target: Impaired Specific Antibody Production
description: Immunoglobulin replacement was given to 7/15 patients in a longitudinal cohort because of infections and impaired antibody responses, even when total IgG was not low. Combined prophylaxis and replacement reduced infection frequency observationally. After HCT, no patient in the transplant cohort required replacement beyond 24 months; earlier post-transplant support may still be needed.
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Because of recurrent infections and dysgammaglobulinemia with poor antibody responses, five patients (33%, P3, P4, P6, P7, P15) received prophylactic antibiotics and seven patients (47%, P3, P6, P7, P9–11, P15) were commenced on immunoglobulin replacement therapy (IgRT) with one receiving via subcutaneous and six via intravenous routes.
explanation: The primary cohort directly documents intravenous and subcutaneous replacement.
- reference: PMID:42529607
reference_title: Allogeneic hematopoietic cell transplantation is curative in CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Similarly, CD19+ B cell deficiency (<200/μl) was reported only in P14 (+26 mo), and no patient required immunoglobulin replacement therapy (IGRT) beyond 24 mo after HCT.
explanation: The full results specify the post-transplant timing.
- name: Antimicrobial Prophylaxis
description: Published cohorts used trimethoprim-sulfamethoxazole and, in selected patients, fluconazole. Azithromycin improved chronic rhinosinusitis and productive cough in one patient. Selection depends on infection history and immune assessment; the evidence is observational.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Antimicrobial Prophylaxis
term:
id: NCIT:C51993
label: Antibiotic Prophylaxis
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: P4 was initiated on trimethoprim-sulfamethoxazole, while P6, P7, P9–11, and P15 were on trimethoprim-sulfamethoxazole and fluconazole prophylaxis.
explanation: The cohort documents antimicrobial prophylaxis.
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: P3 was on azithromycin prophylaxis, and chronic rhinosinusitis and productive cough benefited from the therapy.
explanation: A patient-level respiratory response was reported.
target_mechanisms:
- target: Failure of Cell-Mediated Control of Chronic Viral and Fungal Infection
description: Published cohorts used trimethoprim-sulfamethoxazole and, in selected patients, fluconazole. Azithromycin improved chronic rhinosinusitis and productive cough in one patient. Selection depends on infection history and immune assessment; the evidence is observational.
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: P4 was initiated on trimethoprim-sulfamethoxazole, while P6, P7, P9–11, and P15 were on trimethoprim-sulfamethoxazole and fluconazole prophylaxis.
explanation: The cohort documents antimicrobial prophylaxis.
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: P3 was on azithromycin prophylaxis, and chronic rhinosinusitis and productive cough benefited from the therapy.
explanation: A patient-level respiratory response was reported.
- name: Topical Treatment of Inflammatory Skin Disease
description: Topical corticosteroids and calcineurin inhibitors have been used for eczema and psoriasiform lesions. Severe or refractory disease requires individualized management.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Topical Treatment of Inflammatory Skin Disease
term:
id: NCIT:C122078
label: Topical Corticosteroid Therapy
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Topical corticosteroids and calcineurin inhibitors are effective in managing eczema and psoriatic lesions, and sun protection helped in cases with photosensitive dermatitis16.
explanation: The cohort describes topical control of skin disease.
target_mechanisms:
- target: Atopic Dermatitis
description: Topical corticosteroids and calcineurin inhibitors have been used for eczema and psoriasiform lesions. Severe or refractory disease requires individualized management.
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Topical corticosteroids and calcineurin inhibitors are effective in managing eczema and psoriatic lesions, and sun protection helped in cases with photosensitive dermatitis16.
explanation: The cohort describes topical control of skin disease.
- name: Medical Treatment of Inflammatory Bowel Disease
description: Mesalamine, corticosteroids and other immunosuppressive or biologic agents have been used, with variable or incomplete responses. Some patients required colectomy after multiple medical therapies failed; infection risks complicate treatment selection.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Medical Treatment of Inflammatory Bowel Disease
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: More commonly used options are mesalazine, sulfasalazine, steroids, azathioprine, and infliximab for IBD.
explanation: The clinical report summarizes drugs used for intestinal inflammation.
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Due to unresponsiveness to immunosuppressants, both underwent colectomy, which resolved their symptoms.
explanation: Refractory disease prompted surgery in two patients.
target_mechanisms:
- target: Inflammatory Bowel Disease
description: Mesalamine, corticosteroids and other immunosuppressive or biologic agents have been used, with variable or incomplete responses. Some patients required colectomy after multiple medical therapies failed; infection risks complicate treatment selection.
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: More commonly used options are mesalazine, sulfasalazine, steroids, azathioprine, and infliximab for IBD.
explanation: The clinical report summarizes drugs used for intestinal inflammation.
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Due to unresponsiveness to immunosuppressants, both underwent colectomy, which resolved their symptoms.
explanation: Refractory disease prompted surgery in two patients.
- name: Colectomy for Refractory Colitis
description: Colectomy resolved intestinal symptoms in two medically refractory patients in the longitudinal cohort. It treats severe colonic disease without correcting the systemic immunodeficiency.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Colectomy for Refractory Colitis
term:
id: NCIT:C15209
label: Colectomy
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Due to unresponsiveness to immunosuppressants, both underwent colectomy, which resolved their symptoms.
explanation: Two patients obtained symptomatic control after medical treatment failure.
target_mechanisms:
- target: Inflammatory Bowel Disease
description: Colectomy resolved intestinal symptoms in two medically refractory patients in the longitudinal cohort. It treats severe colonic disease without correcting the systemic immunodeficiency.
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Due to unresponsiveness to immunosuppressants, both underwent colectomy, which resolved their symptoms.
explanation: Two patients obtained symptomatic control after medical treatment failure.
- name: Correction of Gastrointestinal Stenosis
description: Pyloric surgery produced symptom resolution in two affected siblings. Pneumatic dilation partially relieved another sibling’s esophageal stricture. Treatment is guided by anatomical obstruction; these responses do not establish a fibrotic mechanism.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Correction of Gastrointestinal Stenosis
term:
id: NCIT:C15329
label: Surgical Procedure
evidence:
- reference: url:https://all-imm.com/index.php/aei/article/view/1595/2445
reference_title: "Gastrointestinal stenosis: an underrecognized complication of CARMIL2 deficiency | Allergologia et Immunopathologia"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Pyloric stenosis occurred at 6 years and was surgically corrected, resulting in complete resolution.
explanation: One twin had complete symptom resolution after surgery.
- reference: url:https://all-imm.com/index.php/aei/article/view/1595/2445
reference_title: "Gastrointestinal stenosis: an underrecognized complication of CARMIL2 deficiency | Allergologia et Immunopathologia"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: At 16 years, he developed progressive dysphagia due to esophageal stricture with associated esophagitis and nodular pangastritis, partially relieved by pneumatic dilation.
explanation: Esophageal dilation provided partial relief.
target_mechanisms:
- target: Pyloric Stenosis
description: Pyloric surgery produced symptom resolution in two affected siblings. Pneumatic dilation partially relieved another sibling’s esophageal stricture. Treatment is guided by anatomical obstruction; these responses do not establish a fibrotic mechanism.
evidence:
- reference: url:https://all-imm.com/index.php/aei/article/view/1595/2445
reference_title: "Gastrointestinal stenosis: an underrecognized complication of CARMIL2 deficiency | Allergologia et Immunopathologia"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Pyloric stenosis occurred at 6 years and was surgically corrected, resulting in complete resolution.
explanation: One twin had complete symptom resolution after surgery.
- reference: url:https://all-imm.com/index.php/aei/article/view/1595/2445
reference_title: "Gastrointestinal stenosis: an underrecognized complication of CARMIL2 deficiency | Allergologia et Immunopathologia"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: At 16 years, he developed progressive dysphagia due to esophageal stricture with associated esophagitis and nodular pangastritis, partially relieved by pneumatic dilation.
explanation: Esophageal dilation provided partial relief.
- target: Esophageal Stenosis
description: Pneumatic dilation partly relieved symptomatic esophageal narrowing.
evidence:
- reference: url:https://all-imm.com/index.php/aei/article/view/1595/2445
reference_title: "Gastrointestinal stenosis: an underrecognized complication of CARMIL2 deficiency | Allergologia et Immunopathologia"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: At 16 years, he developed progressive dysphagia due to esophageal stricture with associated esophagitis and nodular pangastritis, partially relieved by pneumatic dilation.
explanation: The patient report records partial response.
- name: Inhaled and Intranasal Corticosteroids
description: Inhaled corticosteroids were used for reversible airway obstruction; intranasal corticosteroids relieved rhinitis in the longitudinal cohort. Asthma may occur without demonstrable allergen sensitization.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Inhaled and Intranasal Corticosteroids
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: P3, P6, P7, and P15 were shown to have reversibility on spirometry and were treated with inhaled corticosteroids.
explanation: The cohort directly records asthma treatment.
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: P3, P7, and P15 (20% of patients) had rhinitis, with chronic nasal congestion and rhinorrhea, which was sensitive to intranasal corticosteroids.
explanation: Rhinitis responded to intranasal corticosteroids.
target_mechanisms:
- target: Asthma
description: Inhaled corticosteroids were used for reversible airway obstruction; intranasal corticosteroids relieved rhinitis in the longitudinal cohort. Asthma may occur without demonstrable allergen sensitization.
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: P3, P6, P7, and P15 were shown to have reversibility on spirometry and were treated with inhaled corticosteroids.
explanation: The cohort directly records asthma treatment.
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: P3, P7, and P15 (20% of patients) had rhinitis, with chronic nasal congestion and rhinorrhea, which was sensitive to intranasal corticosteroids.
explanation: Rhinitis responded to intranasal corticosteroids.
- target: Rhinitis
description: Intranasal corticosteroids relieved rhinitis in the cohort.
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: P3, P7, and P15 (20% of patients) had rhinitis, with chronic nasal congestion and rhinorrhea, which was sensitive to intranasal corticosteroids.
explanation: The cohort records symptom response.
- name: Interleukin-2 Supplementation
description: Experimental IL-2 supplementation improves stimulated patient-cell CD25 expression, interferon-gamma output and, in some assays, proliferation. Responses vary with patient, cell subset and time point; CD25 induction can remain below control levels. These are in vitro rescue findings, with no demonstrated clinical efficacy.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Interleukin-2 Supplementation
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:32201938
reference_title: Exogenous interleukin-2 can rescue in-vitro T cell activation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: When cells derived from CARMIL2-deficient patients were treated with IL-2, CD25 and IFN-γ production increased in a dose-dependent manner.
explanation: The primary study measured dose-dependent cellular rescue.
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: CD25 upregulation following anti-CD3/CD28 stimulation of PBMCs was also increased by exogenous IL-2, however it did not reach the levels of healthy control cells (Fig.
explanation: Not every activation endpoint normalized.
target_mechanisms:
- target: Reduced Stimulated T Cell Proliferation
description: Experimental IL-2 supplementation improves stimulated patient-cell CD25 expression, interferon-gamma output and, in some assays, proliferation. Responses vary with patient, cell subset and time point; CD25 induction can remain below control levels. These are in vitro rescue findings, with no demonstrated clinical efficacy.
evidence:
- reference: PMID:32201938
reference_title: Exogenous interleukin-2 can rescue in-vitro T cell activation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: When cells derived from CARMIL2-deficient patients were treated with IL-2, CD25 and IFN-γ production increased in a dose-dependent manner.
explanation: The primary study measured dose-dependent cellular rescue.
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: CD25 upregulation following anti-CD3/CD28 stimulation of PBMCs was also increased by exogenous IL-2, however it did not reach the levels of healthy control cells (Fig.
explanation: Not every activation endpoint normalized.
- name: Glutamine Supplementation
description: Glutamine improved NF-kB and mTOR signaling in stimulated patient CD4 T cells and increased IL17A RNA. Proliferation improved in two patients with abolished baseline responses, but not in two with partially preserved responses; secreted IL-17 was not significantly increased. No patient-treatment efficacy was established.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Glutamine Supplementation
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:40738287
reference_title: CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Glutamine supplementation restored NF-κB and mTOR activity, as measured by p-65 and RPS6 phosphorylation, respectively, and upregulated the expression of IL17A in CARMIL2-mutated CD4+ T cells.
explanation: The study reports cellular signaling rescue, not a clinical trial.
- reference: url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf
reference_title: "https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf"
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Glutamine supplementation improv ed proliferation only in T cells in which proliferati ve ca - pacity was completely abolished before the treatment (patients 1 and 4) ( Fig 4 , H ).
explanation: Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. Proliferation rescue was confined to two severely impaired patient cultures.
- reference: url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf
reference_title: "https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf"
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: T cells deri ve d from 2 other patients (patients 8 and 9) maintained partial proliferati v e capacity , which was not improv ed by glutamine supplementation ( Fig 4 , H ; Fig E3 , D ).
explanation: Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. Two partially responsive patient cultures did not improve.
target_mechanisms:
- target: Reduced Activated T Cell mTOR Signaling
description: Glutamine improved NF-kB and mTOR signaling in stimulated patient CD4 T cells and increased IL17A RNA. Proliferation improved in two patients with abolished baseline responses, but not in two with partially preserved responses; secreted IL-17 was not significantly increased. No patient-treatment efficacy was established.
evidence:
- reference: PMID:40738287
reference_title: CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Glutamine supplementation restored NF-κB and mTOR activity, as measured by p-65 and RPS6 phosphorylation, respectively, and upregulated the expression of IL17A in CARMIL2-mutated CD4+ T cells.
explanation: The study reports cellular signaling rescue, not a clinical trial.
- reference: url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf
reference_title: "https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf"
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Glutamine supplementation improv ed proliferation only in T cells in which proliferati ve ca - pacity was completely abolished before the treatment (patients 1 and 4) ( Fig 4 , H ).
explanation: Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. Proliferation rescue was confined to two severely impaired patient cultures.
- reference: url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf
reference_title: "https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf"
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: T cells deri ve d from 2 other patients (patients 8 and 9) maintained partial proliferati v e capacity , which was not improv ed by glutamine supplementation ( Fig 4 , H ; Fig E3 , D ).
explanation: Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. Two partially responsive patient cultures did not improve.
- name: Dupilumab for Refractory Dermatitis
description: Disease-specific experience is limited and mixed. A published metabolic-study case had marked skin worsening after three months of dupilumab; this observation does not support routine efficacy or establish that all patients will worsen.
therapeutic_modality: MONOCLONAL_ANTIBODY
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: Dupilumab
term:
id: NCIT:C162455
label: Dupilumab
evidence:
- reference: url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf
reference_title: "https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf"
supports: REFUTE
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: (H) Deterioration of skin rash of patient 1 after 3 months of treatment with dupilumab.
explanation: Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. Worsening in one patient argues against assuming dermatitis improvement with dupilumab; it does not establish universal harm.
target_mechanisms:
- target: Atopic Dermatitis
description: Disease-specific experience is limited and mixed. A published metabolic-study case had marked skin worsening after three months of dupilumab; this observation does not support routine efficacy or establish that all patients will worsen.
evidence:
- reference: url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf
reference_title: "https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf"
supports: REFUTE
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: (H) Deterioration of skin rash of patient 1 after 3 months of treatment with dupilumab.
explanation: Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. This case did not demonstrate the intended reduction of dermatitis.
differential_diagnoses:
- name: CD28 deficiency
description: >-
Isolated CD28 deficiency shares impaired costimulation, warts and low memory T-cell and Treg counts.
The reported human phenotype is substantially narrower than CARMIL2 deficiency.
distinguishing_features:
- CARMIL2 deficiency has a broader infection and inflammatory phenotype in reported cohorts.
- Reduced NK and memory B-cell compartments and poor vaccine responses favor CARMIL2 deficiency, although no single laboratory abnormality is obligatory.
- EBV-positive smooth-muscle tumors and intestinal inflammation are characteristic concerns in CARMIL2 deficiency.
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood
counts of CD4+ and CD8+ memory T cells and CD4+ TREGs.
explanation: The shared features that make the two easy to confuse.
quote_role: PRIMARY_RESULT
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody
responses are weak.
explanation: The discriminating laboratory features.
quote_role: PRIMARY_RESULT
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory
bowel disease.
explanation: >-
The discriminating clinical features, absent from CD28 deficiency.
quote_role: PRIMARY_RESULT
- name: Very early onset inflammatory bowel disease of other monogenic cause
description: >-
Very early onset colitis may reflect several monogenic immune disorders. CARMIL2 testing is particularly
relevant when immune dysregulation, viral skin disease or impaired costimulation accompanies intestinal
disease.
distinguishing_features:
- Failed T cell proliferation and activation specifically on CD3/CD28 co-stimulation points to the CD28 axis rather than to another monogenic IBD gene
- Absent or reduced CARMIL2 protein on immunoblot or flow cytometry
- Accompanying recalcitrant warts, molluscum contagiosum and dermatitis
evidence:
- reference: PMID:31115454
reference_title: CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects
in immune-related genes.
explanation: >-
Background establishes monogenic immune disease as a differential for very early onset colitis.
quote_role: BACKGROUND
- reference: PMID:31115454
reference_title: CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation,
consistent with CARMIL2 deficiency.
explanation: The functional test that resolves the differential.
quote_role: PRIMARY_RESULT
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
The largest published characterization assembled 89 individuals from 52 unrelated families originating
from 23 countries; a 2026 transplantation series puts the cumulative literature count at an estimated
120 patients. No population rate has been estimated, and the disease is reported almost entirely from
consanguineous kindreds, so the numbers reflect ascertainment as much as occurrence.
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We established biological and clinical phenotypes of CARMIL2 deficiency by studying 89 individuals
from 52 unrelated families (Table S1) originating from 23 countries.
explanation: >-
Gives the individual and family count of the largest published series. No normalized population
rate is asserted.
quote_role: PRIMARY_RESULT
animal_models:
- name: Rltpr bas L432P Mouse
species: Mouse
genotype: Homozygous Rltpr bas L432P missense allele
publication: PMID:23793062
description: >-
ENU-derived L432P mice show defective CD28 costimulation, reduced Tregs and impaired T-dependent antibody
responses. Reduced protein dosage alone does not explain the phenotype because heterozygous-null mice
with similar protein abundance retain responses.
evidence:
- reference: PMID:23793062
reference_title: The lymphoid lineage-specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We found that Rltpr was a lymphoid cell-specific, actin-uncapping protein essential for costimulation
via CD28 and the development of regulatory T cells.
explanation: >-
Establishes the model as informative for both the co-stimulation and the regulatory T cell nodes.
quote_role: PRIMARY_RESULT
modeled_mechanisms:
- target: Loss of CARMIL2 Scaffolding of CD28 to CARD11
relationship: RECAPITULATES
fidelity: HIGH
description: >-
The mutant protein reaches the synapse with CD28 but fails to connect it to protein kinase C-theta
and Carma1, which is precisely the scaffolding failure this node describes.
limitations: >-
The allele is a point mutant from a mutagenesis screen rather than one of the human disease alleles,
and the human disease is caused by absent or degraded protein at least as often as by a hypomorphic
one. The scaffolding conclusion was subsequently confirmed directly in human T cells, so the model
is not the sole support for this node.
readouts:
- name: CD28 connection to protein kinase C-theta and Carma1
target: Loss of CARMIL2 Scaffolding of CD28 to CARD11
description: >-
Whether CD28 engagement at the immunological synapse recruits its two key downstream effectors
in mutant versus wild-type T cells.
direction: ABOLISHED
interpretation: >-
Loss of the connection with preserved colocalization is the observation that identifies the lesion
as scaffolding rather than localization.
evidence:
- reference: PMID:23793062
reference_title: The lymphoid lineage-specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
However, the connection between CD28 and protein kinase C-θ and Carma1, two key effectors of
CD28 costimulation, was abrogated in T cells expressing mutant Rltpr, and CD28 costimulation
did not occur in those cells.
explanation: Reports the measurement behind this readout.
quote_role: PRIMARY_RESULT
evidence:
- reference: PMID:23793062
reference_title: The lymphoid lineage-specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
However, the connection between CD28 and protein kinase C-θ and Carma1, two key effectors of CD28
costimulation, was abrogated in T cells expressing mutant Rltpr, and CD28 costimulation did not
occur in those cells.
explanation: >-
Supports treating this model as informative for the scaffolding node.
quote_role: PRIMARY_RESULT
- target: Regulatory T Cell Deficit
relationship: RECAPITULATES
fidelity: HIGH
description: >-
The model has reduced Treg development; residual Tregs are present.
limitations: >-
The mouse does not reproduce the mucocutaneous and intestinal inflammation that the human Treg deficit
is invoked to explain, so it supports the cellular node without testing the edge that runs from
it to tissue disease.
evidence:
- reference: PMID:23793062
reference_title: The lymphoid lineage-specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We found that Rltpr was a lymphoid cell-specific, actin-uncapping protein essential for costimulation
via CD28 and the development of regulatory T cells.
explanation: >-
Supports treating the model as informative for the regulatory T cell node.
quote_role: PRIMARY_RESULT
- target: B Cell Receptor-Proximal NF-kB Signaling Failure
relationship: FAILS_TO_RECAPITULATE
fidelity: MODERATE
description: Mouse B-cell proliferative responses and T-independent antibody responses were preserved.
limitations: The measured mouse endpoints do not reproduce the human selective BCR defect; normal proliferation is not a direct measurement of every NF-kB component.
evidence:
- reference: PMID:27647348
reference_title: The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: Mice deprived of functional RLTPR molecules had normal numbers of B cells, and cross-linking of the BCR of such B cells induced their proliferation to the same extent as WT B cells.
explanation: Anti-IgM proliferation was preserved.
- reference: PMID:27647348
reference_title: The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: Rltprbas/bas and WT mice showed similar responses to TNP-LPS (Fig. 9 C).
explanation: TNP-LPS antibody responses were preserved.
- name: Rltpr Null Mouse
species: Mouse
genotype: Deletion of Rltpr exons 1–3
publication: PMID:27647348
description: Complete Rltpr loss impairs costimulation and reduces regulatory and effector-memory CD4 T cells; not all human immune or inflammatory findings occur.
modeled_mechanisms:
- target: Regulatory T Cell Deficit
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: Regulatory-cell abundance is reduced.
limitations: Residual Tregs remain, CD8 memory is relatively preserved and overt autoimmune inflammation is not reproduced.
evidence:
- reference: PMID:27647348
reference_title: The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: Likewise, the spleens of Rltpr−/− mice had approximately one third as many Foxp3+ T reg cells as WT spleen had (Fig. 3 D).
explanation: The deletion model was used to assess Rltpr-dependent immune phenotypes.
evidence:
- reference: PMID:27647348
reference_title: The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: Likewise, the spleens of Rltpr−/− mice had approximately one third as many Foxp3+ T reg cells as WT spleen had (Fig. 3 D).
explanation: The deletion model was used to assess Rltpr-dependent immune phenotypes.
- name: Rltpr CPI-Motif Mutant Mouse
species: Mouse
genotype: Capping-protein-binding CPI motif substitutions
publication: PMID:27647348
description: Selective CPI disruption separates actin-capping-protein interaction from the scaffolding function required for costimulation.
modeled_mechanisms:
- target: Loss of CARMIL2 Scaffolding of CD28 to CARD11
relationship: FAILS_TO_RECAPITULATE
fidelity: MODERATE
description: Disruption of the CPI motif does not abolish CD28 costimulation or Treg development.
limitations: This domain-specific separation-of-function mutant is not equivalent to complete CARMIL2 loss.
evidence:
- reference: PMID:27647348
reference_title: The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: Our data demonstrated, however, that the RLTPR CPI motif is dispensable for co-stimulation via CD28 and the development of T reg and effector memory CD4+ T cells.
explanation: The negative phenotype shows that capping-protein interaction is dispensable for these outputs.
evidence:
- reference: PMID:27647348
reference_title: The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: Our data demonstrated, however, that the RLTPR CPI motif is dispensable for co-stimulation via CD28 and the development of T reg and effector memory CD4+ T cells.
explanation: The negative phenotype shows that capping-protein interaction is dispensable for these outputs.
- name: Carmil2QE gain-of-function knock-in mouse
species: Mouse
genotype: Carmil2QE knock-in, modelling a CARMIL2 substitution found in human T cell malignancies
publication: PMID:40402149
description: >-
Carmil2 QE gain-of-function mice form preassembled CARMIL2-CARD11 complexes and can restore many antigen-dependent
functions in Cd28-null mice. This is a pathway perturbation, not an autosomal recessive deficiency
model.
evidence:
- reference: PMID:40402149
reference_title: A CARMIL2 gain-of-function mutation suffices to trigger most CD28 costimulatory functions in vivo.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Such ready-made CARMIL2QE-CARD11 complexes also formed in CD28-deficient mice where they unexpectedly
induced most of the functions that normally result from CD28 engagement in a manner that remains
antigen-dependent.
explanation: >-
The epistasis result that makes the model informative for the scaffolding node.
quote_role: PRIMARY_RESULT
modeled_mechanisms:
- target: Loss of CARMIL2 Scaffolding of CD28 to CARD11
relationship: PERTURBS
fidelity: MODERATE
description: >-
A gain-of-function perturbation of the same node the disease loses. It does not model the disease
state; it tests, in the opposite direction, whether the CARMIL2-CARD11 complex is the operative
element of CD28 co-stimulation.
limitations: >-
Treg numbers were restored more fully than suppressive activity, which remained about twofold reduced;
iNKT development was not rescued. Mouse NK counts were restored, but this does not explain all differences
between human CD28 and CARMIL2 deficiencies. Solid-tumor assays did not model EBV-positive smooth-muscle
tumors.
evidence:
- reference: PMID:40402149
reference_title: A CARMIL2 gain-of-function mutation suffices to trigger most CD28 costimulatory functions in vivo.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In conclusion, we uncovered the overarching role played by CARMIL2-CARD11 signals among those
triggered by CD28 and exploited them to induce potent solid tumor-specific T cell responses in
the absence of CD28 ligands and immune checkpoint inhibitors.
explanation: >-
The authors' conclusion that CARMIL2-CARD11 is the dominant arm of CD28 signalling, which is the
claim this entry's central chain depends on.
quote_role: PRIMARY_RESULT
- target: Regulatory T Cell Deficit
relationship: RESCUES
fidelity: MODERATE
description: The gain-of-function allele restores regulatory-cell numbers in Cd28-null mice.
limitations: Suppressive function remained about twofold reduced, and iNKT development was not restored.
evidence:
- reference: PMID:40402149
reference_title: A CARMIL2 gain-of-function mutation suffices to trigger most CD28 costimulatory functions in vivo.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: They had, however, a twofold reduced suppressive activity as compared to those of WT and Carmil2QE mice (Fig. 5 C).
explanation: Cell numbers and suppressive function did not recover equivalently.
- reference: PMID:40402149
reference_title: A CARMIL2 gain-of-function mutation suffices to trigger most CD28 costimulatory functions in vivo.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: Consistent with these results, the lack of CARMIL2 had no deleterious effect on iNKT cell development and the expression of CARMIL2QE molecules in Carmil2QECd28−/− thymi failed to restore iNKT cell development (Fig. 3, I and J).
explanation: Some CD28-dependent outputs remain CARMIL2-independent.
- target: Reduced Natural Killer Cell Count
relationship: RESCUES
fidelity: MODERATE
description: The QE allele restores splenic NK counts in Cd28-null mice.
limitations: Human CD28-deficient patients can have normal NK counts; a mouse homeostasis result does not establish the human NK mechanism.
evidence:
- reference: PMID:40402149
reference_title: A CARMIL2 gain-of-function mutation suffices to trigger most CD28 costimulatory functions in vivo.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: The spleen of Cd28−/− and Carmil2−/− mice contained 1.5-fold reduced numbers of the NK cell as compared to the WT spleen, whereas the Carmil2QECd28−/− spleen expressed normal NK cell numbers (Fig. 4 G).
explanation: Mouse genetic comparisons support CARMIL2-dependent NK homeostasis.
- name: Naturally Occurring Canine CARMIL2 R291Ter
species: Dog
genotype: Homozygous CARMIL2 p.R291Ter in Cavalier King Charles Spaniels
publication: PMID:38535207
description: Three dogs with a homozygous nonsense variant had opportunistic or refractory pneumonia and gastrointestinal or skin manifestations. Two had Pneumocystis pneumonia and one had refractory Bordetella pneumonia.
modeled_mechanisms:
- target: Failure of Cell-Mediated Control of Chronic Viral and Fungal Infection
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
description: The naturally occurring canine disorder partially parallels human susceptibility to infection.
limitations: Protein abundance and lymphocyte function were not measured, so the signaling mechanism is inferred from genotype and clinical parallels. Nine other dogs with Pneumocystis infection lacked the variant.
evidence:
- reference: PMID:38535207
reference_title: A Novel CARMIL2 Immunodeficiency Identified in a Subset of Cavalier King Charles Spaniels with Pneumocystis and Bordetella Pneumonia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: Here, we report the discovery of a CARMIL2 nonsense variant in three Cavalier King Charles Spaniel dogs with either PCP (n = 2) or refractory Bordetella pneumonia (n = 1).
explanation: The primary veterinary report describes three affected dogs.
- reference: PMID:38535207
reference_title: A Novel CARMIL2 Immunodeficiency Identified in a Subset of Cavalier King Charles Spaniels with Pneumocystis and Bordetella Pneumonia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: Future studies to quantify CARMIL2 protein production and delineate the functional implications of this variant on host immunity are warranted.
explanation: The authors explicitly identify missing functional measurements.
evidence:
- reference: PMID:38535207
reference_title: A Novel CARMIL2 Immunodeficiency Identified in a Subset of Cavalier King Charles Spaniels with Pneumocystis and Bordetella Pneumonia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: Here, we report the discovery of a CARMIL2 nonsense variant in three Cavalier King Charles Spaniel dogs with either PCP (n = 2) or refractory Bordetella pneumonia (n = 1).
explanation: The primary veterinary report describes three affected dogs.
- reference: PMID:38535207
reference_title: A Novel CARMIL2 Immunodeficiency Identified in a Subset of Cavalier King Charles Spaniels with Pneumocystis and Bordetella Pneumonia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: Future studies to quantify CARMIL2 protein production and delineate the functional implications of this variant on host immunity are warranted.
explanation: The authors explicitly identify missing functional measurements.
datasets:
- accession: GEO:GSE169506
title: Dual T cell– and B cell–intrinsic deficiency in humans [CD4+ T cell SubSeries]
description: Human lymphocyte RNA sequencing includes stimulation experiments comparing healthy controls, CARMIL2-deficient patients and a CD28-deficient comparator. Assay subsets and stimuli differ across samples.
data_type: BULK_RNA_SEQ
publication: PMID:36515678
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: The raw and processed RNA-seq data are available from GEO under SuperSeries accession number GSE169506.
explanation: The primary publication supplies the public accession.
discussions:
- discussion_id: gap_carmil2_beyond_cd28
prompt: >-
Which of CARMIL2's non-CD28 functions accounts for the parts of the phenotype that CD28 deficiency
does not have - the low NK cell counts, the low memory B cells, the weak antibody responses, and the
EBV-positive smooth muscle tumours?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#B Cell Receptor-Proximal NF-kB Signaling Failure
- pathophysiology#Impaired Specific Antibody Production
- pathophysiology#Uncontrolled EBV Infection of Smooth Muscle
- phenotypes#Reduced Natural Killer Cell Count
- phenotypes#Decreased Memory B Cell Proportion
rationale: >-
Patient B-cell assays establish a selective BCR-to-NF-kB defect. NK degranulation can also be impaired,
and 2025 mouse genetics implicates CARMIL2/CD28 signaling in NK homeostasis. However, normal NK counts
in human CD28 deficiency, variable NK lymphopenia in CARMIL2 deficiency, and the absence of direct
EBV-smooth-muscle tumor killing assays leave the human tumor-surveillance mechanism unresolved.
proposed_experiments:
- experiment_id: exp_carmil2_nk_cell_intrinsic_requirement
name: Cell-intrinsic requirement for CARMIL2 in NK cells
description: >-
Determine whether the NK cell deficit is NK-cell-intrinsic by testing CARMIL2-dependent receptor
signalling in patient NK cells directly, and by comparing NK reconstitution kinetics after transplantation
with those of the T cell compartment.
- experiment_id: exp_carmil2_pkc_receptor_panel
name: Which protein kinase C-coupled receptors need CARMIL2
description: >-
Test NF-kB activation in patient T, B and NK cells across a panel of receptors that signal through
protein kinase C to CARD11, to establish whether CARMIL2 is a general requirement for that route
or is specific to a subset of receptors.
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak.
explanation: Human phenotypes extend beyond isolated CD28 deficiency.
- reference: PMID:40402149
reference_title: A CARMIL2 gain-of-function mutation suffices to trigger most CD28 costimulatory functions in vivo.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: The spleen of Cd28−/− and Carmil2−/− mice contained 1.5-fold reduced numbers of the NK cell as compared to the WT spleen, whereas the Carmil2QECd28−/− spleen expressed normal NK cell numbers (Fig. 4 G).
explanation: Mouse genetics provides a partial mechanism for NK-cell homeostasis.
- discussion_id: gap_carmil2_cytoskeletal_defect_contested
prompt: >-
Do CARMIL2-deficient human T cells actually have a migration defect, and does any such defect contribute
to disease?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Perturbed T Cell Cytoskeletal Organization
rationale: >-
The earlier study measured cytoskeletal organization, speed, directionality and chemotaxis, whereas
the later high-density collagen assay reported normal morphology. These are different readouts under
different matrix conditions. The evidence supports context dependence rather than a universal contradiction;
clinical consequences remain unproven.
proposed_experiments:
- experiment_id: exp_carmil2_migration_assay_reconciliation
name: Head-to-head migration assays in CARMIL2-deficient T cells
description: >-
Run the assays behind both results side by side on the same patient cells - interstitial and transendothelial
migration, polarity and uropod formation, and the three-dimensional collagen assay - reporting velocity
and directionality as well as morphology, to establish whether the discrepancy is assay-dependent
or patient-dependent.
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix.
explanation: Patient T cells retained normal morphology in high-density collagen.
- discussion_id: gap_carmil2_metabolic_rescue_translation
prompt: >-
Can bypassing the broken co-stimulatory signal downstream - with interleukin-2 or with glutamine -
do anything useful for patients who cannot be transplanted?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Reduced Stimulated T Cell Proliferation
- pathophysiology#Reduced Activated T Cell mTOR Signaling
- treatments#Interleukin-2 Supplementation
- treatments#Glutamine Supplementation
rationale: >-
IL-2 and glutamine improve selected patient-cell readouts in culture, but response depends on baseline
impairment, stimulus and endpoint. Glutamine increased signaling and IL17A RNA without a significant
secreted IL-17 increase, and proliferation improved in only two of four assayed patients. Neither
intervention has established clinical efficacy or safety in CARMIL2 deficiency. Controlled studies
would need endpoints beyond acute signaling rescue.
proposed_experiments:
- experiment_id: exp_carmil2_bypass_agent_comparison
name: Compare the two ex vivo rescues on common readouts
description: >-
Test interleukin-2 and glutamine supplementation, alone and together, on the same panel of patient
cells with common readouts - NF-kB and mTOR activity, proliferation, Th1 and Th17 cytokine output
- to establish whether they act on the same bottleneck and whether either restores the Th17 arm
that the mucosal fungal phenotype depends on.
evidence:
- reference: PMID:32201938
reference_title: Exogenous interleukin-2 can rescue in-vitro T cell activation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: In conclusion, we found that IL-2 rescued T cell activation and proliferation in CARMIL2-deficient patients.
explanation: The primary authors propose further study of IL-2.
- reference: PMID:40738287
reference_title: CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Glutamine supplementation restored NF-κB and mTOR activity, as measured by p-65 and RPS6 phosphorylation, respectively, and upregulated the expression of IL17A in CARMIL2-mutated CD4+ T cells.
explanation: The glutamine study reports cellular signaling rescue.
- reference: url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf
reference_title: "https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf"
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Glutamine supplementation improv ed proliferation only in T cells in which proliferati ve ca - pacity was completely abolished before the treatment (patients 1 and 4) ( Fig 4 , H ).
explanation: Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. Proliferation rescue was confined to two severely impaired patient cultures.
- reference: url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf
reference_title: "https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf"
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: T cells deri ve d from 2 other patients (patients 8 and 9) maintained partial proliferati v e capacity , which was not improv ed by glutamine supplementation ( Fig 4 , H ; Fig E3 , D ).
explanation: Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. Two partially responsive patient cultures did not improve.
notes: >-
Naming. The MONDO label calls this "severe combined immunodeficiency due to CARMIL2 deficiency"; the primary literature calls it a combined immunodeficiency (CID) without the "severe", and the distinction is substantive rather than stylistic. SCID is defined by the absence of autologous T cells; CARMIL2-deficient patients have normal total CD3+, CD4+ and CD8+ counts and a functional defect in the memory and regulatory subsets. The entry is therefore named CARMIL2 Deficiency, the MONDO label is retained as a synonym, and the mapping is kept as an exact match because it is the same concept under a label this entry disputes.

Phenotype term choices worth a second look. Three bindings are broader than the finding they carry, and in each case the alternative was worse. The EBV-positive smooth muscle tumour is bound to HP:0031459 Soft tissue neoplasm: HPO has no smooth-muscle-tumour term that leaves malignant potential open, and the available alternatives either assert benignity (HP:0031460 Benign muscle neoplasm) or name a specific site or malignancy the disease does not have. Inflammatory bowel disease is bound to HP:0002583 Colitis, HPO having no generic IBD term. Dermatitis is bound to HP:0001047 Atopic dermatitis although the reported range runs from atopic and seborrhoeic through to psoriasiform; the cohort does not report the subtypes separately, so splitting into three phenotypes would manufacture a breakdown the source does not give. In all three cases `preferred_term` carries the more accurate name.

Not curated for want of a citable quantitative source: peripheral eosinophilia and raised IgE are both described in CARMIL2 deficiency and would fit the Th2 bias this entry does curate, but the papers cached here state them only in passing or in patient tables rather than in a quotable propositional sentence.

Frequency bands are all taken from one prospective 15-patient cohort (PMID:34287962), which is the only source found that reports per-manifestation rates. A cohort of 15 gives wide confidence intervals on every band, and the same cohort's skin figure of 93 per cent aggregates warts, molluscum and dermatitis, so the individual skin phenotypes are banded conservatively. The 89-patient series does not report manifestation frequencies in its abstract.

Model coverage is uneven and deliberately so. There is a good mouse model of the molecular lesion and of the regulatory T cell deficit, and a striking gain-of-function mouse that tests the scaffolding claim in the opposite direction, but no model curated here reproduces the EBV-driven tumours, the inflammatory bowel disease, or the cutaneous viral phenotype - which is to say, no model reproduces anything a patient actually presents with. This is not a gap in the curation; it is the state of the field, and it is why the `gap_carmil2_beyond_cd28` discussion proposes no experiment in an animal. Full-text evidence also cites the authors’ deposited PDF at https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf; DOI:10.1016/j.jaci.2025.07.018 identifies the same article. Full-text quotations also cite the publisher HTML at https://all-imm.com/index.php/aei/article/view/1595/2445; this is the same article.
references:
- reference: PMID:23793062
title: The lymphoid lineage-specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells.
- reference: PMID:27647348
title: The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells.
- reference: PMID:27647349
title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
- reference: PMID:27896283
title: A potential founder variant in CARMIL2/RLTPR in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction.
- reference: PMID:28112205
title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
- reference: PMID:29479355
title: Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency.
- reference: PMID:31115454
title: CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease.
- reference: PMID:32201938
title: Exogenous interleukin-2 can rescue in-vitro T cell activation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation.
- reference: PMID:32625199
title: A Novel Pathogenic Variant in CARMIL2 (RLTPR) Causing CARMIL2 Deficiency and EBV-Associated Smooth Muscle Tumors.
- reference: PMID:34287962
title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
- reference: PMID:36515678
title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
- reference: PMID:38535207
title: A Novel CARMIL2 Immunodeficiency Identified in a Subset of Cavalier King Charles Spaniels with Pneumocystis and Bordetella Pneumonia.
- reference: PMID:39649299
title: Secondary Membranous Nephropathy and Immunodeficiency due to a Novel Biallelic Variant in CARMIL2.
- reference: PMID:40402149
title: A CARMIL2 gain-of-function mutation suffices to trigger most CD28 costimulatory functions in vivo.
- reference: PMID:40738287
title: CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation.
- reference: PMID:42529607
title: Allogeneic hematopoietic cell transplantation is curative in CARMIL2 deficiency.
- reference: DOI:10.15586/aei.v54i3.1595
title: "Gastrointestinal stenosis: an underrecognized complication of CARMIL2 deficiency"
- reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0055cbc0-64df-4f38-9074-495f4ac74e1c-2024-03-12T160000.000Z
title: curation results for Gene-Disease Validity
experimental_models:
- name: Patient T Cell Costimulation and Isoform Complementation
experimental_model_type: PRIMARY_CELL_CULTURE
cell_source: Patient-derived primary cells
description: Primary patient T cells stimulated with CD3/CD28 or PMA, with lentiviral re-expression of functional isoform 3. This addresses limitations of PTEN-deficient Jurkat cells.
publication: PMID:36515678
modeled_mechanisms:
- target: Failure of CD28-Dependent Canonical NF-kB Activation
relationship: RESCUES
fidelity: MODERATE
description: Isoform 3 restored NF-kB activation after both stimuli.
limitations: Cultured-cell rescue does not establish clinical gene-therapy efficacy; isoform 1 did not provide equivalent complementation.
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Impaired NF-κB activation upon stimulation with PMA and CD3/CD28 was rescued in primary T cells by the transduction of CARMIL2-deficient cells with the WT CARMIL2 isoform 3, but not by transduction with an empty vector (Fig. 4 I).
explanation: Primary-cell genetic rescue identifies functional CARMIL2 dependence.
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Impaired NF-κB activation upon stimulation with PMA and CD3/CD28 was rescued in primary T cells by the transduction of CARMIL2-deficient cells with the WT CARMIL2 isoform 3, but not by transduction with an empty vector (Fig. 4 I).
explanation: Primary-cell genetic rescue identifies functional CARMIL2 dependence.
- name: CARMIL2-Deficient Jurkat Variant Assays
experimental_model_type: CELL_LINE
cell_source: Engineered human Jurkat T-cell line
description: Knockout Jurkat cells complemented with wild-type or patient alleles quantify protein abundance and CD28-induced NF-kB activity.
publication: PMID:36515678
modeled_mechanisms:
- target: Failure of CD28-Dependent Canonical NF-kB Activation
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: Patient alleles impaired CD28 signaling in complementation assays.
limitations: Immortalized Jurkat cells lack PTEN; primary-cell confirmation is important. Overexpression in HEK293T cells does not reproduce all lymphocyte stability defects.
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28.
explanation: Functional allele testing establishes impaired costimulation.
evidence:
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28.
explanation: Functional allele testing establishes impaired costimulation.
- name: Patient B Cell Receptor Stimulation
experimental_model_type: PRIMARY_CELL_CULTURE
cell_source: Patient-derived primary cells
description: Patient B cells stimulated with anti-IgM, CD40 ligand or PMA distinguish receptor-specific signaling defects.
publication: PMID:27647349
modeled_mechanisms:
- target: B Cell Receptor-Proximal NF-kB Signaling Failure
relationship: RECAPITULATES
fidelity: MODERATE
description: Anti-IgM-induced NF-kB activation is impaired while CD40 responses remain intact.
limitations: ERK is relatively preserved; this assay does not isolate the full contribution of T-cell help to antibody deficiency.
evidence:
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Interestingly, although anti-IgM Abs induced NF-κB activation in controls, BCR engagement of RLTPR-deficient B cells failed to induce IκBα degradation or phosphorylation of P65.
explanation: The experiment identifies selective BCR-to-NF-kB failure.
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: These data show that RLTPR-deficient B cells have a partially defective signaling pathway, at least via NF-κB, but an intact CD40 signaling pathway, at least for the readouts tested.
explanation: A preserved alternative signaling route bounds the defect.
evidence:
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Interestingly, although anti-IgM Abs induced NF-κB activation in controls, BCR engagement of RLTPR-deficient B cells failed to induce IκBα degradation or phosphorylation of P65.
explanation: The experiment identifies selective BCR-to-NF-kB failure.
- reference: PMID:27647349
reference_title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: These data show that RLTPR-deficient B cells have a partially defective signaling pathway, at least via NF-κB, but an intact CD40 signaling pathway, at least for the readouts tested.
explanation: A preserved alternative signaling route bounds the defect.
- name: Patient T Cell Cytoskeleton and Migration Assays
experimental_model_type: PRIMARY_CELL_CULTURE
cell_source: Patient-derived primary cells
description: Cultured patient T cells show altered microtubule organization, leading-edge actin distribution and migration directionality.
publication: PMID:28112205
modeled_mechanisms:
- target: Perturbed T Cell Cytoskeletal Organization
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: Patient-cell assays support a directional migration defect despite increased spontaneous speed.
limitations: Total F-actin, LFA1 and CXCR4 were preserved. Assays do not establish the contribution to infection or tumor risk.
evidence:
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Although migrating with increased speed that resulted in higher accumulated migratory distance (Supplementary Fig. 7h), CARMIL2-deficient T-cell migration was less orientated with a markedly decreased directness (Fig. 8h) and reduced Euclidean distance (Supplementary Fig. 7i,j).
explanation: Directional movement was measured in patient-cell assays.
evidence:
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Although migrating with increased speed that resulted in higher accumulated migratory distance (Supplementary Fig. 7h), CARMIL2-deficient T-cell migration was less orientated with a markedly decreased directness (Fig. 8h) and reduced Euclidean distance (Supplementary Fig. 7i,j).
explanation: Directional movement was measured in patient-cell assays.
- name: Patient T Cells in Dense Three-Dimensional Collagen
experimental_model_type: PRIMARY_CELL_CULTURE
cell_source: Patient-derived primary cells
description: A later study assessed morphology during migration in collagen at approximately three times the earlier concentration.
publication: PMID:34287962
modeled_mechanisms:
- target: Perturbed T Cell Cytoskeletal Organization
relationship: FAILS_TO_RECAPITULATE
fidelity: MODERATE
description: Cells had normal morphology in this assay.
limitations: The negative morphology result does not refute every prior velocity, microtubule or chemotaxis endpoint; matrix density and assay outputs differ.
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix.
explanation: Patient T cells retained normal morphology in high-density collagen.
evidence:
- reference: PMID:34287962
reference_title: Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix.
explanation: Patient T cells retained normal morphology in high-density collagen.
- name: Patient NK Cell K562 Degranulation Assay
experimental_model_type: CO_CULTURE
cell_source: Patient-derived primary cells
description: Patient NK cells challenged with K562 targets before and after IL-2 pretreatment.
publication: PMID:28112205
modeled_mechanisms:
- target: Reduced Natural Killer Cell Degranulation
relationship: RECAPITULATES
fidelity: MODERATE
description: K562-induced degranulation and NKG2D expression were reduced.
limitations: This assay does not directly test EBV-positive smooth-muscle tumor killing; IL-2 pretreatment abolished measured differences.
evidence:
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: NK-cell degranulation in response to co-incubation with the erythroleukemic cell line K562 was impaired and accompanied by a decreased expression of NKG2D.
explanation: The target-cell assay shows impaired NK degranulation.
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: NK cell and CD8 T-cell pre-culturing with IL-2 abrogated the observed differences in degranulation and NKG2D expression (Fig. 6).
explanation: The phenotype is stimulus- and treatment-dependent.
evidence:
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: NK-cell degranulation in response to co-incubation with the erythroleukemic cell line K562 was impaired and accompanied by a decreased expression of NKG2D.
explanation: The target-cell assay shows impaired NK degranulation.
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: NK cell and CD8 T-cell pre-culturing with IL-2 abrogated the observed differences in degranulation and NKG2D expression (Fig. 6).
explanation: The phenotype is stimulus- and treatment-dependent.
- name: IL-2 Rescue of Patient T Cells
experimental_model_type: PRIMARY_CELL_CULTURE
cell_source: Patient-derived primary cells
description: Exogenous IL-2 added to activated patient lymphocytes improves selected activation and proliferation readouts.
publication: PMID:32201938
modeled_mechanisms:
- target: Reduced Stimulated T Cell Proliferation
relationship: RESCUES
fidelity: MODERATE
description: Proliferation improves in responsive patient cultures.
limitations: Some patients had normal baseline proliferation; rescue is endpoint-specific, and Treg expansion was not established.
evidence:
- reference: PMID:32201938
reference_title: Exogenous interleukin-2 can rescue in-vitro T cell activation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: In conclusion, we found that IL-2 rescued T cell activation and proliferation in CARMIL2-deficient patients.
explanation: The primary study reports in vitro rescue.
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: CD25 upregulation following anti-CD3/CD28 stimulation of PBMCs was also increased by exogenous IL-2, however it did not reach the levels of healthy control cells (Fig.
explanation: CD25 remained below healthy-control levels in the later study.
evidence:
- reference: PMID:32201938
reference_title: Exogenous interleukin-2 can rescue in-vitro T cell activation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: In conclusion, we found that IL-2 rescued T cell activation and proliferation in CARMIL2-deficient patients.
explanation: The primary study reports in vitro rescue.
- reference: PMID:36515678
reference_title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: CD25 upregulation following anti-CD3/CD28 stimulation of PBMCs was also increased by exogenous IL-2, however it did not reach the levels of healthy control cells (Fig.
explanation: CD25 remained below healthy-control levels in the later study.
- name: Patient CD4 T Cell Metabolic Profiling and Glutamine Rescue
experimental_model_type: PRIMARY_CELL_CULTURE
cell_source: Patient-derived primary cells
description: RNA sequencing, metabolite profiling and signaling assays after activation show altered metabolic programs and response to added glutamine. Nine patients were recruited, with smaller subsets in each assay.
publication: PMID:40738287
modeled_mechanisms:
- target: Impaired Activation-Induced T Cell Metabolic Reprogramming
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: Patient cells show altered metabolic transcripts and metabolite abundance.
limitations: RNA sequencing used four patients and three controls; metabolomics used six and eight. Abundance is not metabolic flux or uptake.
evidence:
- reference: PMID:40738287
reference_title: CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: RNA sequencing of CD4+ T cells revealed decreased expression of genes associated with metabolic activity, including mTOR signaling, glycolysis, 1-carbon metabolism, and glutamine metabolism.
explanation: Metabolic transcriptional changes were measured.
- reference: PMID:40738287
reference_title: CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Whole-cell metabolomics reinforced these results and highlighted glutamine deficiency as a potential driver of the observed metabolic phenotype.
explanation: Metabolite profiling provides a second readout.
- target: Reduced Activated T Cell mTOR Signaling
relationship: RESCUES
fidelity: MODERATE
description: Glutamine increased RPS6 phosphorylation.
limitations: Only two of four patients in the proliferation assay improved; increased IL17A RNA did not establish increased secreted IL-17 or clinical benefit.
evidence:
- reference: PMID:40738287
reference_title: CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Glutamine supplementation restored NF-κB and mTOR activity, as measured by p-65 and RPS6 phosphorylation, respectively, and upregulated the expression of IL17A in CARMIL2-mutated CD4+ T cells.
explanation: The rescue readouts are signaling and transcript expression.
- reference: url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf
reference_title: "https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf"
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Glutamine supplementation improv ed proliferation only in T cells in which proliferati ve ca - pacity was completely abolished before the treatment (patients 1 and 4) ( Fig 4 , H ).
explanation: Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. Proliferation rescue was confined to two severely impaired patient cultures.
- reference: url:https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf
reference_title: "https://ronharellab.technion.ac.il/wp-content/uploads/sites/450/2026/01/2025-J-Allergy-Clin-Immunol.pdf"
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: T cells deri ve d from 2 other patients (patients 8 and 9) maintained partial proliferati v e capacity , which was not improv ed by glutamine supplementation ( Fig 4 , H ; Fig E3 , D ).
explanation: Authors’ full-text copy of PMID:40738287, CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation. Two partially responsive patient cultures did not improve.
evidence:
- reference: PMID:40738287
reference_title: CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: RNA sequencing of CD4+ T cells revealed decreased expression of genes associated with metabolic activity, including mTOR signaling, glycolysis, 1-carbon metabolism, and glutamine metabolism.
explanation: Metabolic transcriptional changes were measured.
- reference: PMID:40738287
reference_title: CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: Whole-cell metabolomics reinforced these results and highlighted glutamine deficiency as a potential driver of the observed metabolic phenotype.
explanation: Metabolite profiling provides a second readout.
- name: Autologous EBV Lymphoblastoid Cell and Patient T Cell Coculture
experimental_model_type: CO_CULTURE
cell_source: Patient peripheral T cells and autologous irradiated EBV-positive lymphoblastoid cells
publication: PMID:28112205
description: Serial coculture tested EBV-responsive T-cell expansion and cytokine output in two patients and healthy controls.
evidence:
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: We found that expansion rates of LCL stimulated T-cell lines (TCL) from P2.1 and P2.2 were significantly lower than from HD (Supplementary Fig. 2a).
explanation: Two patient T-cell lines expanded poorly with autologous EBV-positive lymphoblastoid targets.
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: TCL from P2.1 and P2.2 did not secrete IFN-γ on stimulation with autologous LCL but secreted IFN-γ on stimulation with phytohemagglutintin (PHA) (Supplementary Fig. 2b).
explanation: EBV-target stimulation failed to induce normal IFN-gamma output.
modeled_mechanisms:
- target: Uncontrolled EBV Infection of Smooth Muscle
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
description: Patient T cells expanded poorly and lacked IFN-gamma secretion to autologous EBV-positive lymphoblastoid cells.
limitations: The target cells are lymphoblastoid cells, not infected smooth-muscle cells or tumors. The experiment supports impaired EBV responses but does not reproduce tumor initiation or directly measure tumor killing.
evidence:
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: We found that expansion rates of LCL stimulated T-cell lines (TCL) from P2.1 and P2.2 were significantly lower than from HD (Supplementary Fig. 2a).
explanation: Two patient T-cell lines expanded poorly with autologous EBV-positive lymphoblastoid targets.
- reference: PMID:28112205
reference_title: A human immunodeficiency syndrome caused by mutations in CARMIL2.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: TCL from P2.1 and P2.2 did not secrete IFN-γ on stimulation with autologous LCL but secreted IFN-γ on stimulation with phytohemagglutintin (PHA) (Supplementary Fig. 2b).
explanation: EBV-target stimulation failed to induce normal IFN-gamma output.

📚

References & Deep Research

References

PMID:23793062

The lymphoid lineage-specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells.

No top-level findings curated for this source.

PMID:27647348

The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells.

No top-level findings curated for this source.

PMID:27647349

Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.

No top-level findings curated for this source.

PMID:27896283

A potential founder variant in CARMIL2/RLTPR in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction.

No top-level findings curated for this source.

PMID:28112205

A human immunodeficiency syndrome caused by mutations in CARMIL2.

No top-level findings curated for this source.

PMID:29479355

Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency.

No top-level findings curated for this source.

PMID:31115454

CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease.

No top-level findings curated for this source.

PMID:32201938

Exogenous interleukin-2 can rescue in-vitro T cell activation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation.

No top-level findings curated for this source.

PMID:32625199

A Novel Pathogenic Variant in CARMIL2 (RLTPR) Causing CARMIL2 Deficiency and EBV-Associated Smooth Muscle Tumors.

No top-level findings curated for this source.

PMID:34287962

Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.

No top-level findings curated for this source.

PMID:36515678

Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.

No top-level findings curated for this source.

PMID:38535207

A Novel CARMIL2 Immunodeficiency Identified in a Subset of Cavalier King Charles Spaniels with Pneumocystis and Bordetella Pneumonia.

No top-level findings curated for this source.

PMID:39649299

Secondary Membranous Nephropathy and Immunodeficiency due to a Novel Biallelic Variant in CARMIL2.

No top-level findings curated for this source.

PMID:40402149

A CARMIL2 gain-of-function mutation suffices to trigger most CD28 costimulatory functions in vivo.

No top-level findings curated for this source.

PMID:40738287

CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells and is partially rescued by glutamine supplementation.

No top-level findings curated for this source.

PMID:42529607

Allogeneic hematopoietic cell transplantation is curative in CARMIL2 deficiency.

No top-level findings curated for this source.

DOI:10.15586/aei.v54i3.1595

Gastrointestinal stenosis: an underrecognized complication of CARMIL2 deficiency

No top-level findings curated for this source.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0055cbc0-64df-4f38-9074-495f4ac74e1c-2024-03-12T160000.000Z

curation results for Gene-Disease Validity

No top-level findings curated for this source.

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References