LAT Deficiency

Mendelian MONDO:0044721 Pathograph 52 Show in embeddings browser Primary Immunodeficiency Combined Immunodeficiency

LAT deficiency is an autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in LAT, the transmembrane adaptor that ZAP-70 phosphorylates once the T-cell receptor is engaged. LAT has no catalytic activity of its own: its cytoplasmic tail carries four tyrosines that, when phosphorylated, become docking sites for PLC-gamma1, Grb2 and Gads, and through Gads for SLP-76. That assembly is where one receptor signal fans out into the calcium, Ras-ERK and transcriptional arms of T-cell activation, so losing the adaptor leaves the receptor intact and every branch below it unserved. The reported human phenotype spans two presentations that are recognisably the same lesion. In one pedigree the picture was typical severe combined immunodeficiency with absent T cells and preserved B and natural killer cells, and a later single patient was reported from a series of typical and atypical SCID without a published immunophenotype. In a consanguineous kindred with a truncating exon 5 variant, three siblings instead presented in the first year with combined immunodeficiency accompanied by severe autoimmune cytopenias, lymphadenopathy and splenomegaly, with T cells present at diagnosis and progressively lost; two died in childhood and the third was transplanted. Both presentations are curated here as one entry because the gene, the inheritance and the signalling lesion are the same, and the IUIS classification carries them as one condition. Two features make the disorder mechanistically interesting beyond its rarity. First, autoimmunity in a disease of failed T-cell activation is not a paradox in this pathway: mouse genetics established that LAT is itself a negative regulator of T-cell responses and homeostasis, and that T cells deprived of it drive lymphoproliferation and autoantibody production in a receptor-independent, quasi-mitogenic fashion. Second, human and mouse do not agree on how severe the developmental block is. Mice lacking LAT, or carrying all four tyrosines mutated, arrest at the DN3 thymocyte stage with no peripheral T cells at all, whereas patients lacking the same four tyrosines still produce mature, if badly differentiated, T cells whose receptors still mobilise calcium and activate NF-kappaB while ERK signalling is abolished. No compensating adaptor has been identified, and that residual signalling remains unexplained.

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Classifications

IUIS Category

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Inheritance

Autosomal recessive HP:0000007

All reported patients are homozygous for truncating LAT variants; the first kindred was born to consanguineous parents of Arab origin, and in the third report the parents were confirmed heterozygous by Sanger sequencing. Heterozygous carriers are clinically well; in the Keller kindred the heterozygous parents and sister had normal lymphocyte subsets, normal immunoglobulins and normal TCR-induced phosphorylation of ZAP-70, ITK and ERK, arguing against a dominant-negative effect of the truncated protein.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:27242165 SUPPORT Human Clinical

"In this study, we describe the first kindred with defective LAT signaling caused by a homozygous mutation in exon 5, leading to a premature stop codon deleting most of the cytoplasmic tail of LAT, including the critical tyrosine residues for signal propagation."

Establishes homozygosity for a truncating LAT allele in the first reported kindred, which is the basis for the recessive classification.

PMID:27242165 SUPPORT Human Clinical

"In T cells of the heterozygous parents and sister, the phosphorylation of ZAP70, ITK, ERK, and Ca2+ mobilization was found to be normal (not depicted), indicating that there is no dominant-negative effect of the mutation in the heterozygous situation."

Documents normal TCR signalling in carriers, which is what makes the inheritance recessive rather than dominant-negative.

Discussions and Knowledge Gaps

Can the LAT-null mouse be used to predict the T-cell compartment of a person with LAT deficiency, when the same loss of all four cytoplasmic tyrosines abolishes peripheral T cells in the mouse but not in patients?

HUMAN MODEL MISMATCH mouse_null_overstates_the_human_developmental_block

Attached to

pathophysiology#Arrest of Thymic T Cell Development animal_models#Lat-null mouse

This is the mismatch the first human report was built around, and it is not a difference of degree at the margins. Mice lacking LAT, and mice in which all four tyrosines are replaced by phenylalanine, arrest at the DN3 stage and have no peripheral T cells. The patients in the first kindred carry an allele that removes those same four tyrosines and still had mature T cells in normal numbers at presentation, with the numbers falling only over subsequent years. Two candidate explanations were tested and neither survived. A compensating adaptor was sought: SIT, TRIM, LAX, LIME and PAG were not differentially expressed in the patients' T cells, NTAL/LAB protein was undetectable, and CD6 transduced into LAT-deficient Jurkat cells did not restore calcium mobilisation. Reversion of the mutation and alternative splicing were both excluded, by sequencing of sorted T cells and by RNA sequencing. So the residual development is unexplained rather than explained by a known substitute. The practical consequence is narrow enough to use. The null mouse is informative about where in thymic development LAT acts and about what the adaptor does biochemically; it is not informative about how many T cells a patient will have, nor about anything that depends on having a peripheral T-cell compartment, which includes the whole autoimmune arm of the human disease. For that arm the tyrosine knock-in strains are the better read.

Show evidence (2 references)

PMID:27242165 SUPPORT Human Clinical

"LAT knockout mice (Zhang et al., 1999b) and mice with targeted replacement of all four tyrosine residues (Sommers et al., 2001) lack peripheral T cells because of a block at the double-negative 3 stage, whereas in humans, T cells lacking all four equivalent tyrosine residues were still present,..."

States both halves of the mismatch in one sentence, naming the mouse alleles that produce the complete block.

PMID:27353087 SUPPORT REVIEW SYNTHESIS Other

"It is possible that some LAT-related molecule might compensate for the loss of LAT function in the human, but efforts to identify such molecules were not productive."

Records that the obvious explanation was looked for and not found, which is why the mismatch is left open.

How do patient T cells lacking all four LAT phosphotyrosines still mobilise calcium and activate NF-kappaB after receptor cross-linking, when the same allele abolishes both in a reconstituted LAT-deficient T-cell line?

KNOWLEDGE GAP residual_calcium_and_nfkb_signalling_is_unexplained

Attached to

pathophysiology#Failure of TCR Signalosome Assembly pathophysiology#Abolished TCR-Induced ERK Activation

Calcium mobilisation downstream of the receptor is supposed to require PLC-gamma1 recruited to the LAT phosphotyrosine at position 132. In the patients' own memory CD4 and CD8 T cells, and in their gamma-delta T cells, calcium flux after CD3 cross-linking was within the range of healthy controls across independent experiments, and IkappaB-alpha degradation proceeded normally, while ERK phosphorylation was absent. The same patient allele expressed in LAT-deficient Jurkat cells abolished calcium flux, so this is a difference between primary human T cells and the cell line rather than between the mutant and the wild-type protein. A partial account exists for why ERK and calcium come apart: the three distal tyrosines recruit Grb2-SOS1 and are required for Ras activation, so a route to PLC-gamma1 that bypasses LAT would give inositol trisphosphate and calcium without giving ERK. What is missing is the route itself. Resolving it matters beyond this disease, because the textbook non-redundancy of LAT in calcium signalling is what the patients contradict.

Show evidence (2 references)

PMID:27242165 SUPPORT Human Clinical

"However, to our surprise, Ca2+ mobilization after CD3 cross-linking was normal in primary T cells of the index patient, and the sustained T cell differentiation in LAT-deficient patients supports the notion of a preserved residual TCR signal in vivo."

States the unexpected preserved calcium response in the patient's primary T cells, which is the gap.

PMID:27242165 SUPPORT Human Clinical

"Therefore, it is unlikely that CD6 replaces LAT function in LAT-deficient primary T cells, and the explanation of the preserved Ca2+ flux, NF-κB activation in the patient’s T cells, and the persistent T cell differentiation remains elusive at this time."

The authors' own statement that the finding is unexplained after the candidate substitutes were tested.

Why does the same class of truncating LAT allele produce absent T cells and typical SCID in one pedigree and present-but-declining T cells with severe autoimmunity in another?

OPEN QUESTION scid_versus_cid_presentation_is_not_yet_explained

Attached to

pathophysiology#Arrest of Thymic T Cell Development pathophysiology#Loss of LAT-Dependent Restraint on T Cell Responses

IUIS records both presentations in a single row, and this entry follows that by curating them together. But the two kindreds are genuinely different at the bedside: one presented as T-negative SCID with normal B and NK cells, the other with normal T-cell numbers, lymphoproliferation and life-threatening autoimmune cytopenias from five months of age. Both alleles are truncating. Three explanations are available and none can be chosen with three kindreds. The alleles truncate at different positions, so a residual product retaining some proximal function is possible in one and not the other. The CID kindred's own course shows that T-cell numbers fall with time, so the difference may be partly one of when the patients were ascertained. And modifier or environmental contributions cannot be excluded in pedigrees of this size. Recording the question rather than a `has_subtypes` split keeps the entry from asserting a stratification the evidence does not yet support.

Show evidence (2 references)

PMID:41608114 SUPPORT Other

The classification committee's own record that both presentations belong to one condition, which is what makes this an open question rather than a lumping error.

PMID:27242165 SUPPORT Human Clinical

"The identification of additional patients with possibly different LAT mutations will shed further light on the full immunological and clinical presentation of human LAT deficiency."

The authors' statement that the phenotypic range is not yet established, which is the state this question records.

Is the lymphoproliferative arm of human LAT deficiency IL-6 dependent, as it is in the LatY136F mouse, and would IL-6 blockade therefore be a rational bridge to transplant?

EMERGING HYPOTHESIS il6_dependence_of_the_lymphoproliferative_arm_is_untested_in_patients

Attached to

pathophysiology#Loss of LAT-Dependent Restraint on T Cell Responses pathophysiology#Polyclonal Lymphoproliferation

In the LatY136F mouse the mutant T cells overproduce IL-6, and crossing the strain onto an IL-6-deficient background showed that IL-6 is required for the uncontrolled early T-cell expansion; the reduction came from impaired cell survival rather than from a further developmental block or more regulatory T cells. Aged IL-6-deficient LatY136F mice eventually hyperproliferated and developed splenomegaly, but with diminished isotype switching and autoantibody production, so IL-6 loss delays and attenuates the syndrome rather than abolishing it. Nothing equivalent has been measured in patients: no IL-6 level, no IL-6 pathway readout, and no anti-IL-6 exposure is reported in any of the three kindreds. The hypothesis is recorded because the autoimmune arm is what kills these children before transplant and there is an approved drug class against this target, not because human evidence supports it. Any use would be off-label, unstudied in this disease, and taken on a mouse result obtained with a different allele.

Show evidence (2 references)

PMID:26034173 SUPPORT INDIRECT Model Organism

"By crossing LATY136F mice with IL-6-deficient mice, we demonstrated that IL-6 is required for uncontrolled T cell expansion during the early stage of disease development."

The genetic experiment behind the hypothesis. INDIRECT because it is a mouse result on a different allele from the human disease-causing ones, and the inference to patients is untested.

PMID:26034173 SUPPORT INDIRECT Model Organism

"In aged IL-6(-/-) LATY136F mice, CD4(+) T cells began to hyperproliferate and induced splenomegaly; however, isotype switching and autoantibody production were diminished."

Records that removing IL-6 attenuates rather than abolishes the syndrome, which is the limit on how much the hypothesis could deliver.

Does loss of LAT contribute to disease through mast cells, megakaryocytes or platelets, in which the adaptor is also expressed but in which no patient has been studied?

KNOWLEDGE GAP non_t_lineage_contribution_is_uncharacterised

Attached to

pathophysiology#Reduced Cytotoxic Degranulation phenotypes#Decreased natural killer cell degranulation

LAT is expressed in mast cells, natural killer cells, megakaryocytes, platelets and early B cells as well as in T cells. The only non-T lineage in which LAT-deficient patients have been assessed is the NK compartment, where degranulation and cytotoxicity were reduced but not absent. No report gives platelet function, bleeding history, mast-cell function or allergic history in a LAT-deficient patient, so whether the expression pattern translates into clinical features outside the T-cell compartment is unknown. This is worth recording rather than leaving implicit because the inference is tempting and unsupported: an adaptor expressed in platelets is not thereby a platelet disease, and the thrombocytopenia the patients did have was autoantibody-mediated, which is a T-cell-driven route to the same laboratory finding. Distinguishing the two would need platelet function testing in a patient, which nobody has published.

Show evidence (2 references)

PMID:16102570 SUPPORT REVIEW SYNTHESIS Other

"Although LAT is also expressed in mast cells, natural killer cells, megakaryocytes, platelets, and early B cells, the present review specifically illustrates the role LAT plays in the development and function of mouse T cells."

Establishes the expression pattern outside T cells that makes the question worth asking.

PMID:27242165 SUPPORT Human Clinical

"Finally, the degranulation of LATmut CTLs after stimulation with anti-CD3/anti-CD28 beads (Fig. 6 D) and of patient-derived NK cells after stimulation with the K562 cell line was reduced (Fig. 6 E), although not absent."

The one non-T lineage measurement that exists in patients, which is where the available human evidence stops.

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Pathophysiology

Biallelic LAT Loss-of-Function Variants

Homozygous truncating LAT variants. The reported alleles are the exon 5 two-base deletion c.268_269delGG, which frameshifts at codon 89 and truncates the protein after 100 of 233 residues; an independent frameshift producing a premature stop codon with complete loss of LAT protein expression; and p.Y207fsTer33. All remove some or all of the cytoplasmic tyrosines. The c.268_269delGG transcript is present at normal levels and the truncated protein can be expressed from a transgene, so the lesion is in the protein's adaptor function rather than in transcription.

LAT hgnc:18874 ⇓ LOSS OF FUNCTION

Genetic context variant_origin: GERMLINE allelic_event: FRAMESHIFT_VARIANT zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Germline biallelic truncating LAT alleles, homozygous in every reported patient, with the parents heterozygous and unaffected wherever they were tested.

Downstream

Loss of the LAT Cytoplasmic Phosphotyrosine Docking Sites Truncation removes the cytoplasmic tail carrying the phosphorylation sites, so no docking platform can be built regardless of upstream kinase activity.

Show evidence (3 references)

PMID:27242165 SUPPORT Human Clinical

"This mutation caused a deletion of guanosines 268/269 in exon 5 of LAT, leading to a frame shift and a premature stop codon after 303 bp (Fig. 2 A)."

Identifies the specific frameshift allele segregating with disease in the first reported kindred.

PMID:27522155 SUPPORT Human Clinical

"Sanger sequencing of the LAT gene showed a mutation that resulted in a premature stop codon and protein truncation leading to complete loss of function and loss of expression of LAT in the affected family members."

Documents an independent truncating allele that abolishes LAT expression, establishing loss of function as the disease mechanism.

PMID:37516813 SUPPORT Human Clinical

"The mutations include RAG2 (p.I273T,p.G44X), IL7R (p.F361WfsTer17), ADA (c.780+1G>A), JAK3 (p.Q228Ter), LIG4 (p.G428R), and LAT (p.Y207fsTer33)"

Adds a third truncating LAT allele from an independent SCID cohort, so the allelic spectrum is not confined to one family.

Loss of the LAT Cytoplasmic Phosphotyrosine Docking Sites

LAT works by being phosphorylated. ZAP-70, activated at the engaged receptor, phosphorylates the tyrosines of the LAT cytoplasmic tail; the resulting phosphotyrosine motifs are SH2-domain binding sites for PLC-gamma1, Grb2 and Gads, with Gads in turn recruiting SLP-76. Truncated LAT retains its extracellular and transmembrane segments and reaches the membrane but presents no phosphotyrosines, so the adaptor function is lost while upstream events are untouched: ZAP-70 phosphorylation is normal in cells expressing the mutant protein.

LAT hgnc:18874 ⇓ LOSS OF FUNCTION

signaling adaptor activity GO:0035591 ⇓ LOSS OF FUNCTION SH2 domain binding GO:0042169 ↓ DECREASED

Downstream

Failure of TCR Signalosome Assembly With no phosphotyrosines to dock on, the PLC-gamma1 and Gads-SLP-76 complexes cannot be nucleated at the membrane.

Show evidence (3 references)

PMID:9489702 SUPPORT In Vitro

"We show that this protein is phosphorylated by ZAP-70/Syk protein tyrosine kinases leading to recruitment of multiple signaling molecules."

The original identification of LAT as the ZAP-70 substrate whose phosphorylation recruits downstream molecules, which is the function the truncation removes.

PMID:26354432 SUPPORT REVIEW SYNTHESIS Other

"These Tyr(P) motifs serve as binding sites for SH2 domain-containing proteins, including PLC-γ1, Grb2, and Gads (14–16), allowing the nucleation of multiple signaling complexes on LAT, which are essential for downstream signaling."

Names the partners the phosphotyrosine motifs recruit, which is what the patients' truncated protein cannot do. Graded OTHER with quote_role REVIEW_SYNTHESIS because the sentence is a review's synthesis of work it did not perform.

PMID:27242165 SUPPORT In Vitro

"After CD3 cross-linking, similar TCR-proximal ZAP70 phosphorylation was observed in LAT-deficient, LATwt-, and LATmut-expressing T cell lines (Fig. 3 A)."

Shows the lesion is at the adaptor and not upstream of it: the kinase that phosphorylates LAT is activated normally in cells carrying the patient allele.

Failure of TCR Signalosome Assembly

The multiprotein complex that normally forms on phosphorylated LAT does not assemble. In cells reconstituted with the patient allele the measurable consequence is that PLC-gamma1 phosphorylation is absent, because PLC-gamma1 recruitment depends on the LAT-SLP-76 signalosome. This is where a single receptor signal would ordinarily be diversified into the calcium and Ras-ERK arms, and it is the step the disease removes.

T cell CL:0000084

T cell receptor signaling pathway GO:0050852 ↓ DECREASED

Downstream

Abolished TCR-Induced ERK Activation The Grb2-SOS arm that drives Ras-ERK is recruited through the same phosphotyrosine motifs.

Arrest of Thymic T Cell Development Pre-TCR and TCR signals that drive thymocyte maturation pass through the same adaptor.

Loss of LAT-Dependent Restraint on T Cell Responses LAT carries negative as well as positive regulatory modules, so its loss removes a brake at the same time as it removes the signal.

Reduced Cytotoxic Degranulation Signalling through LAT is beneficial, though not essential, for granule release by cytotoxic lymphocytes.

Show evidence (3 references)

PMID:27242165 SUPPORT In Vitro

"In line with the literature that PLCγ1 phosphorylation depends on the assembly of the LAT-SLP76 signalosome (Smith-Garvin et al., 2009), PLCγ1 phosphorylation was absent in J.CaM2.5 and J.CaM2.5-LATmut cells (Fig. 3 A)."

Demonstrates in LAT-deficient Jurkat cells reconstituted with the patient allele that the signalosome-dependent step fails.

PMID:27522155 SUPPORT In Vitro

"We also demonstrate loss of LAT expression and lack of TCR signaling restoration in LAT-deficient cell lines reconstituted with a synthetic LAT gene bearing this severe combined immunodeficiency mutation."

An independent reconstitution experiment showing the patient allele cannot restore TCR signalling, which is the functional definition of this node.

PMID:17534068 SUPPORT REVIEW SYNTHESIS Other

"LAT coordinates the assembly of a multiprotein signalling complex through phosphotyrosine-based motifs present within its intracytoplasmic segment. The resulting 'LAT signalosome' links the TCR to the main intracellular signalling pathways that regulate T cell development and T cell function."

States what the signalosome is and what it connects, which is the structure this node says fails to form.

Abolished TCR-Induced ERK Activation

ERK phosphorylation after receptor cross-linking is absent both in the patients' own T cells and in cells reconstituted with the patient allele. This is the branch of the cascade the human disease loses cleanly, and it is what distinguishes LAT deficiency from the neighbouring T-cell signalling defects: the calcium and NF-kappaB arms are preserved in the patients' residual T cells while ERK is not.

CD4-positive, alpha-beta T cell CL:0000624

ERK1 and ERK2 cascade GO:0070371 ↓ DECREASED

Downstream

Impaired T Cell Activation and Proliferation ERK output is required for the activation programme that follows receptor engagement.

Show evidence (2 references)

PMID:27242165 SUPPORT Human Clinical

"Despite the reported nonredundant role of LAT in Ca(2+) mobilization, residual T cells were able to induce Ca(2+) influx and nuclear factor (NF) κB signaling, whereas extracellular signal-regulated kinase (ERK) signaling was completely abolished."

States the selective loss of ERK signalling in patient T cells alongside preserved calcium and NF-kappaB responses.

PMID:27242165 SUPPORT Human Clinical

"the phosphorylation of ERK was absent in LATmut-expressing CD4 T cell subpopulations (Fig. 4 C)"

The measurement behind the node, made directly in the patient's CD4 T cells.

Arrest of Thymic T Cell Development

LAT is required for the signals that carry thymocytes through development. In mice the requirement is absolute and the block sits at the CD25+CD44- DN3 stage, with no peripheral T cells at all. In people the block is partial and variable: one pedigree had absent T cells with preserved B and NK cells, a T-B+NK+ SCID immunophenotype, while in the kindred with the exon 5 truncation T cells were present in normal numbers at presentation and fell over years. Both are recorded here; the species difference is taken up in `discussions`.

thymocyte CL:0000893

T cell differentiation in thymus GO:0033077 ↓ DECREASED

Animal models

Lat-null mouse Mouse partially recapitulates Reproduces the requirement for LAT in thymic development, and locates the checkpoint, but at a severity the human disease does not reach.

Downstream

Severe combined immunodeficiency Absent thymic output produces the T-negative, B-positive, NK-positive SCID presentation.

Decreased total T cell count

Show evidence (2 references)

PMID:27522155 SUPPORT Human Clinical

"We describe a pedigree affected by a severe combined immunodeficiency phenotype with absent T cells and normal B-cell and natural killer cell numbers."

The human end of the claim: a LAT-mutant pedigree with no T cells and intact B and NK compartments.

PMID:10204488 SUPPORT INDIRECT Model Organism

"Flow cytometric analysis revealed normal B cell populations but the absence of any mature peripheral T cells. Intrathymic development was blocked within the CD4- CD8- stage."

Establishes where in thymic development the requirement for LAT sits. Graded INDIRECT because the stage of the block is shown in mice and the human block is demonstrably less complete.

Loss of LAT-Dependent Restraint on T Cell Responses

The counterintuitive arm of the disease. LAT is not only a positive conductor of receptor signals; it is also a negative regulator of TCR signalling and T-cell homeostasis, and T cells deprived of it mount self-perpetuating responses. Mouse genetics shows this directly: deleting LAT from post-thymic CD4 T cells, or replacing the PLC-gamma1 docking tyrosine, produces a lymphoproliferative disorder with excessive cytokine production and autoantibodies rather than a quiescent immunodeficiency, and the expansion is receptor-independent rather than driven by self-reactive clones. The patients show the corresponding clinical picture, with lymphoproliferation and severe autoimmune cytopenias from the first year of life.

CD4-positive, alpha-beta T cell CL:0000624

T cell homeostasis GO:0043029 ↓ DECREASED

Animal models

LatY136F knock-in mouse Mouse partially recapitulates Reproduces the central paradox of the human disease: an allele that impairs receptor signalling produces lymphoproliferation and autoimmunity rather than immunological silence.

Downstream

Polyclonal Lymphoproliferation

Th2 Effector Skewing Weak or absent TCR signalling through LAT biases effector differentiation toward type 2 cytokine production.

Peripheral Gamma-Delta T Cell Expansion

Show evidence (4 references)

PMID:19682930 SUPPORT INDIRECT Model Organism

"The fact that such LAT-independent signals result in lymphoproliferative disorders with excessive cytokine production demonstrates that LAT constitutes a key negative regulator of the triggering module and of the LAT-independent branches of the TCR signaling cassette."

States the negative-regulator role that makes autoimmunity a predicted rather than paradoxical consequence of losing LAT. INDIRECT because the demonstration is in conditionally LAT-deleted mouse T cells.

PMID:18209052 SUPPORT INDIRECT Model Organism

"These results argue against a scenario where the Lat(Y136F) pathology is primarily due to a lack of functional Foxp3(+) regulatory T cells and suggest that a defect intrinsic to Lat(Y136F) CD4 T cells leads to a state of TCR-independent hyperactivity."

Locates the defect inside the T cell rather than in regulatory T-cell control, which is what makes this a loss of intrinsic restraint.

PMID:20542732 SUPPORT REVIEW SYNTHESIS Other

"In the absence of LAT, antigen-specific T cells give rise to self-perpetuating pro-inflammatory responses and induce the production of autoantibodies independently of TCR engagement."

A review's synthesis of the mouse work, stating the mechanism by which loss of a positive signalling adaptor yields immune pathology.

+ 1 more reference

Impaired T Cell Activation and Proliferation

The T cells that do reach the periphery cannot be activated. Receptor cross-linking induces only reduced levels of CD69, ICOS and CD25, and co-stimulation through CD28 does not rescue it; proliferation to anti-CD3 and anti-CD3/CD28 is abrogated and to phytohaemagglutinin strongly reduced.

CD4-positive, alpha-beta T cell CL:0000624 CD8-positive, alpha-beta T cell CL:0000625

T cell activation GO:0042110 ↓ DECREASED T cell proliferation GO:0042098 ↓ DECREASED

Downstream

Susceptibility to Severe and Opportunistic Infection

Defective T-Dependent Antibody Production

Decreased anti-CD3/28-induced T-cell proliferation

Decreased T cell activation

Show evidence (2 references)

PMID:27242165 SUPPORT Human Clinical

"Anti-CD3 stimulation for 20 h induced only reduced levels of CD69, inducible T cell co-stimulator (ICOS), and CD25 in LATmut T cells, which could not be increased by the addition of anti-CD28 (Fig. 6 B)."

Measures the activation failure in the patient's own T cells and shows co-stimulation does not compensate.

PMID:27242165 SUPPORT Human Clinical

"Similarly, in vitro proliferation of CD4 T cells (Fig. 6 C) and CD8 T cells (not depicted) after stimulation with anti-CD3, anti-CD3/anti-CD28 was abrogated and strongly reduced after PHA compared with the control."

The proliferation half of the node, in patient cells against day controls.

Reduced Cytotoxic Degranulation

Granule release by the patients' cytotoxic lymphocytes is reduced but not absent: CD107a upregulation on CD8 T cells after bead stimulation and on NK cells after exposure to K562 targets was below control, and NK-cell cytotoxicity in the oldest sibling was diminished. The partial rather than complete defect matches mouse work showing LAT is beneficial but not essential for degranulation, and this is the only non-T lineage in which patients have been tested.

CD8-positive, alpha-beta T cell CL:0000625 natural killer cell CL:0000623

Downstream

Decreased CD8+ T cell degranulation

Decreased natural killer cell degranulation

Susceptibility to Severe and Opportunistic Infection Reduced cytotoxic output contributes to the failure to clear virally infected cells, alongside the activation defect.

Show evidence (2 references)

PMID:27242165 SUPPORT INDIRECT BACKGROUND Model Organism

"This might reflect previous results from mice that signaling via LAT is not essential but beneficial for the process of degranulation"

The sentence in which the reporting authors attribute the partial rather than complete degranulation defect to the mouse result. Graded MODEL_ORGANISM because the evidence it describes is murine, with quote_role BACKGROUND because the citing paper is restating it rather than reporting it.

PMID:27242165 SUPPORT Human Clinical

Reports both degranulation measurements and their partial character, which is what this node claims.

Th2 Effector Skewing

A high proportion of the patients' memory CD4 T cells produce interleukin-4 without stimulation, and the same excess of spontaneous IL-4 producers appears in their expanded gamma-delta compartment. The corresponding mouse mutant accumulates helper T cells chronically producing type 2 cytokines, with tissue eosinophilia and massive IgE and IgG1 plasma cell maturation, so the skew is a reproducible consequence of weakened signalling through this adaptor rather than an incidental finding in one patient.

T-helper 2 cell CL:0000546 ↑ INCREASED

T-helper 2 cell differentiation GO:0045064 ↑ INCREASED

Animal models

LatY136F knock-in mouse Mouse recapitulates The type 2 skew is reproduced in full, and was described in the model before it was observed in patients.

Downstream

Polyclonal B Cell Activation and Autoantibody Production Type 2 helper output drives the B-cell activation arm.

Increased circulating IgE concentration

Show evidence (2 references)

PMID:27242165 SUPPORT Human Clinical

"In accordance with LAT-deficient mice, a high percentage of LATmut-expressing CD4 T cells constitutively produced IL-4, implying an expansion of the T helper type 2 cell (Th2) phenotype (Fig. 6 A)."

The human observation of constitutive IL-4 production by the patient's CD4 T cells.

PMID:12065839 SUPPORT INDIRECT Model Organism

"However, later they accumulated polyclonal helper T (TH) cells that chronically produced type 2 cytokines in large amounts."

The mouse counterpart of the same skew, cited as corroboration rather than as evidence about patients.

Peripheral Gamma-Delta T Cell Expansion

Every patient in the Keller kindred had a striking excess of circulating gamma-delta T cells, up to 80% of the T-cell pool in one, and the expanded population was skewed away from the normally dominant Vdelta2 subset toward Vdelta1 and Vdelta3. Mouse mutants carrying targeted mutations of the three distal tyrosines expand gamma-delta T cells in spleen and lymph node, which is the closest model counterpart; complete LAT loss in mice instead abolishes peripheral gamma-delta T cells altogether.

gamma-delta T cell CL:0000798 ↑ INCREASED

gamma-delta T cell proliferation GO:0046630 ↑ INCREASED

Downstream

Increased gamma-delta T cell proportion

Show evidence (2 references)

PMID:27242165 SUPPORT Human Clinical

"A common finding in all patients was the remarkable increase of γδ T cells."

States the finding and that it was present in all three patients of the kindred.

PMID:27242165 SUPPORT Human Clinical

"Unlike in healthy individuals, the most abundant circulating Vδ2-positive γδ T cell population was nearly absent in patient 2 (Fig. 7 A), and in line with this finding, Vγ9-positive cells were <5% (not depicted)."

Records the repertoire skew within the expanded compartment, which is what makes this more than a numerical increase.

Polyclonal Lymphoproliferation

Lymphadenopathy and splenomegaly were present in all three patients of the first kindred from infancy, one required splenectomy, and lymph node histology showed distorted architecture with poorly formed follicles and no Bcl6-positive germinal centres.

T cell CL:0000084

Downstream

Lymphadenopathy

Splenomegaly

Hepatomegaly

Absence of lymph node germinal center

Dermal Lymphocytic Infiltration

Progressive Immune Collapse The two older patients' lymphocyte counts and immunoglobulins fell over years, after a period of normal values, in the setting of sustained dysregulation and repeated infection. The authors read the decline as secondary to that combination rather than to a defined mechanism, so the link is recorded with unknown intermediates.

Show evidence (2 references)

PMID:27242165 SUPPORT Human Clinical

"The histological examination of lymph nodes from patients 1 and 2 showed distorted architecture with poorly formed follicles (not depicted)."

The tissue-level correlate of the lymphoproliferation, in two of the three patients.

PMID:12065840 SUPPORT INDIRECT Model Organism

"Mice homozygous for a single tyrosine mutation in LAT (linker for activation of T cells) exhibited an early block in T cell maturation but later developed a polyclonal lymphoproliferative disorder and signs of autoimmune disease."

Establishes in the model that the same lesion produces a developmental block and a later lymphoproliferative disorder, which is the combination the patients show.

Dermal Lymphocytic Infiltration

Persistent red to purple oedematous skin nodules on the face and forearms were present in the two older siblings. Biopsy showed extensive lymphoid infiltration of the dermis, sparing the epidermis, mainly by CD8 T cells, with in situ hybridisation for EBV-encoded RNA negative and no fungi or acid-fast bacteria, so the lesions are infiltrative rather than infectious.

CD8-positive, alpha-beta T cell CL:0000625

Downstream

Skin nodule

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"The skin biopsies showed extensive lymphoid infiltration of the dermis but not the epidermis, mainly by CD8 T cells."

The histological basis for this node and for its restriction to the dermis.

Polyclonal B Cell Activation and Autoantibody Production

Autoantibody-mediated disease dominates the clinical picture of the CID presentation: Coombs-positive autoimmune haemolytic anaemia, immune thrombocytopenia and autoimmune neutropenia, and in the youngest sibling a fatal anti-ADAMTS13-positive thrombotic microangiopathy. The mouse tyrosine mutant supplies the mechanism, in which aberrant helper T cells drive polyclonal, antigen-independent B-cell activation and systemic autoimmunity.

B cell CL:0000236

B cell activation GO:0042113 ↑ INCREASED

Animal models

LatY136F knock-in mouse Mouse partially recapitulates Supplies the step from aberrant helper T cells to polyclonal, non-antigen driven B-cell activation and systemic autoimmunity.

Downstream

Autoimmune hemolytic anemia

Autoimmune thrombocytopenia

Autoimmune neutropenia

Anti-ADAMTS13 antibody positivity The ADAMTS13 autoantibody is one of the autoantibodies this node produces, and it is what drives the thrombotic microangiopathy below.

Show evidence (2 references)

PMID:16887989 SUPPORT INDIRECT Model Organism

"In Lat(Y136F) mice, B cell activation was polyclonal and not Ag-driven because the increase in serum IgG1 and IgE concentrations involved Abs and autoantibodies with different specificities equally."

Supplies the polyclonal, antigen-independent character of the B-cell activation. INDIRECT because it is established in the mouse tyrosine mutant rather than in patients.

PMID:27242165 SUPPORT Human Clinical

"Patient 1 presented at the age of 5 mo with the first severe episode of Coombs-positive autoimmune hemolytic anemia and immune-mediated thrombocytopenia, lymphadenopathy, and massive splenomegaly."

The human autoantibody-mediated disease this node stands for, with its age of onset.

Defective T-Dependent Antibody Production

Helper function fails along with the rest of T-cell activation. Serum immunoglobulins were normal or high in early childhood in the CID kindred and then fell: one patient developed hypogammaglobulinaemia with partially reduced specific antibody responses at four years, and another progressed to panhypogammaglobulinaemia requiring replacement. Class-switched and IgM memory B cells were strongly reduced and lymph node germinal centres were absent.

B cell CL:0000236

immunoglobulin production GO:0002377 ↓ DECREASED

Downstream

Panhypogammaglobulinemia

Decreased class-switched memory B cell proportion

Show evidence (2 references)

PMID:27242165 SUPPORT Human Clinical

"At the age of 4 yr, he developed hypogammaglobulinemia with partially reduced specific antibody responses."

Records the loss of antibody production and of specific responses in a patient whose immunoglobulins had previously been normal.

PMID:27242165 SUPPORT Human Clinical

"Absolute and relative numbers of B cells were reduced, and a relative increase of transitional B cells was observed, whereas class-switched and IgM memory B cells were strongly decreased."

The B-cell compartment correlate of failed T-dependent help.

Susceptibility to Severe and Opportunistic Infection

Without functional T-cell immunity the patients cannot control common or opportunistic pathogens. The reported infections are recurrent pneumonia from infancy, cytomegalovirus viraemia in all three siblings of the first kindred, adenovirus, varicella, Candida pneumonia, congenital toxoplasmosis, Epstein-Barr viraemia, and in the youngest sibling urinary infections and gastroenteritis. Two of the three died of infection or its consequences, one of disseminated CMV while awaiting transplant.

T cell CL:0000084

Downstream

Recurrent pneumonia

Severe cytomegalovirus infection

Opportunistic infection

Recurrent urinary tract infections

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"For progressive treatment–resistant autoimmune cytopenia, he was splenectomized at the age of 7 yr, but at age 9, awaiting hematopoietic stem cell transplantation, he died because of disseminated CMV infection with pulmonary involvement."

The clinical consequence of the infection susceptibility, including its fatal outcome in one patient.

Progressive Immune Collapse

A second phase of the CID presentation, and what makes the disease progressive rather than static. Both older siblings began with normal lymphocyte counts and immunoglobulins, then lost T cells, B cells and immunoglobulin over several years while autoimmunity and infection continued. The youngest sibling died at two years, before reaching this phase.

T cell homeostasis GO:0043029 ↓ DECREASED

Downstream

Decreased total lymphocyte count

Decreased total B cell count

Decreased total CD4+ T cell count

Panhypogammaglobulinemia

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"During the progression of the disease, the immune systems of the two older patients seemed to collapse, lymphocytopenia and hypogammaglobulinemia developed, and opportunistic as well as other infections occurred."

States the progressive attrition directly, and that it followed a period of normal counts.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Blood 16

Decreased total T cell count HP:0005403

Show evidence (2 references)

PMID:41608114 SUPPORT Other

The IUIS row records the T-cell count for LAT deficiency as normal to low, which is the variability this phenotype describes.

PMID:27242165 SUPPORT Human Clinical

"Unlike in the mouse counterpart, reduced numbers of T cells were present in the patients."

States the reduced but non-zero T-cell counts of the CID kindred.

Decreased total CD4+ T cell count HP:5210418

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"CD4 T cells were severely decreased, especially affecting the naive CD4 T cell subpopulation, whereas the percentage of regulatory T cells and circulating T follicular helper cell populations showed minor changes (Table 2)."

Records the CD4 deficit and locates it in the naive compartment.

Increased gamma-delta T cell proportion HP:0500270

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"An increased number of γδ T cells (up to 80% of T cells) was noted on several occasions."

Quantifies the gamma-delta excess in one of the patients.

Decreased T cell activation HP:0005419

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

The activation-marker measurement in the patient's own T cells that this phenotype names.

Decreased anti-CD3/28-induced T-cell proliferation HP:0031382

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

The measurement this phenotype names, made in patient cells.

Decreased CD8+ T cell degranulation HP:0025835

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

Reports the cytotoxic T-lymphocyte degranulation defect directly.

Decreased natural killer cell degranulation HP:0025807

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"Accordingly, NK cells of patient 1 showed diminished cytotoxicity compared with day controls (not depicted)."

Records the NK functional defect in a second patient, alongside the degranulation assay in the index patient.

Autoimmune hemolytic anemia HP:0001890

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"Patient 1 presented at the age of 5 mo with the first severe episode of Coombs-positive autoimmune hemolytic anemia and immune-mediated thrombocytopenia, lymphadenopathy, and massive splenomegaly."

Names the Coombs-positive haemolytic anaemia and its age of onset.

Autoimmune thrombocytopenia HP:0001973

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"Autoimmunity | Coombs+ AIHA, ITP, autoimmune neutropenia | Coombs+ AIHA, ITP | Anti-ADAMTS13+ microangiopathic hemolytic anemia"

The autoimmunity row of the clinical summary table, recording immune thrombocytopenia in the two older siblings.

Autoimmune neutropenia HP:0001904

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"Autoimmunity | Coombs+ AIHA, ITP, autoimmune neutropenia | Coombs+ AIHA, ITP | Anti-ADAMTS13+ microangiopathic hemolytic anemia"

The autoimmunity row of the clinical summary table, which records autoimmune neutropenia in the first patient.

Microangiopathic hemolytic anemia HP:0001937

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"At the age of 2 yr, she died of anti-ADAMTS13–positive microangiopathic hemolytic anemia and thrombocytopenia."

Names the microangiopathic haemolysis and its fatal outcome.

Panhypogammaglobulinemia HP:0003139

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"Ig levels dropped from hypergammaglobulinemia with normal IgA and IgM to panhypogammaglobulinemia."

Documents the fall to panhypogammaglobulinaemia in the index patient.

Increased circulating IgE concentration HP:0003212

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"The immunological evaluation of patient 3 at the age of 2 yr was remarkable for hypergammaglobulinemia and elevated IgE."

Records the raised IgE in the third patient.

Decreased class-switched memory B cell proportion HP:0030388

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"Absolute and relative numbers of B cells were reduced, and a relative increase of transitional B cells was observed, whereas class-switched and IgM memory B cells were strongly decreased."

Names the class-switched memory B-cell deficit.

Decreased total lymphocyte count HP:0001888

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"At the age of 8 yr, patient 2 had developed panlymphopenia leading to strongly reduced absolute counts of all B and CD4 T cell subpopulations."

Records the panlymphopenia and the subsets it affected.

Decreased total B cell count HP:0010976

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"Given the initial records of normal numbers of B and NK cells in patient 2 and normal Ig levels in all siblings at a younger age, the latter changes are likely to be secondary to progressive immune dysregulation."

Records both the fall in B cells and the authors' reading of it as a secondary change.

Cardiovascular 3

Lymphadenopathy HP:0002716

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"Lymphoproliferation | Lymphadenopathy, splenomegaly | Lymphadenopathy, splenomegaly | Lymphadenopathy, splenomegaly"

The lymphoproliferation row of the clinical summary table, recording lymphadenopathy in each of the three patients.

Splenomegaly HP:0001744

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"Like his brother, he suffered from hepatosplenomegaly, lymphadenopathy, and persistent red edematous nodules on his forearms."

Records splenic enlargement, here as hepatosplenomegaly, in the index patient.

Absence of lymph node germinal center HP:0002849

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"Aggregates of small, CD20-positive cells were associated with CD21-positive follicular dendritic cells, but Bcl6-positive germinal centers were absent."

The histological finding this phenotype names, in lymph nodes from two patients.

Digestive 1

Hepatomegaly HP:0002240

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"Like his brother, he suffered from hepatosplenomegaly, lymphadenopathy, and persistent red edematous nodules on his forearms."

Records hepatosplenomegaly in the index patient, of which liver enlargement is the hepatic component.

Genitourinary 1

Recurrent urinary tract infections HP:0000010

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"Recurrent pneumonia, urinary infections, gastroenteritis, CMV viremia"

The infection row of the clinical summary table for the third patient, whose plural "urinary infections" is what supports the recurrent binding.

Immune 5

Severe combined immunodeficiency HP:0004430

Show evidence (1 reference)

PMID:27522155 SUPPORT Human Clinical

"We describe a pedigree affected by a severe combined immunodeficiency phenotype with absent T cells and normal B-cell and natural killer cell numbers. A novel homozygous frameshift mutation in the gene encoding for LAT was identified in this kindred."

Names the SCID phenotype and its immunophenotype in a LAT-mutant pedigree.

Recurrent pneumonia HP:0006532

Sequelae: Bronchiectasis

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"From 1 yr of age, he suffered from recurrent respiratory tract infections, which progressed to chronic lung disease with bronchiectasis."

Documents the recurrent respiratory infection and the structural lung damage it produced.

Severe cytomegalovirus infection HP:0031692

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"At age 7 yr, varicella infection was diagnosed, and shortly after, he developed CMV and adenoviral infection with severe progressive deterioration of respiratory function."

Records severe CMV disease with respiratory deterioration in the index patient.

Opportunistic infection HP:0031690

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

States that opportunistic infection was part of the clinical course.

Anti-ADAMTS13 antibody positivity HP:6000462

Sequelae: Microangiopathic hemolytic anemia

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"At the age of 2 yr, she died of anti-ADAMTS13–positive microangiopathic hemolytic anemia and thrombocytopenia."

Records the ADAMTS13 autoantibody directly.

Integument 1

Skin nodule HP:0200036

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"Like his brother, he suffered from hepatosplenomegaly, lymphadenopathy, and persistent red edematous nodules on his forearms."

Names the skin nodules and their persistence in the index patient.

Respiratory 1

Bronchiectasis HP:0002110

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"He had additionally suffered from chronic lung disease with bronchiectasis and disseminated purple edematous skin lesions on his face and arms."

Names bronchiectasis in the oldest sibling.

🧬

Genetic Associations

LAT

Gene: LAT hgnc:18874 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:27242165 SUPPORT Human Clinical

"12 homozygous variants remained, but only chr16:28997725 deletion (del) GG (RefSeq accession no. NM_001014987.1: c.268_269del) segregated with the disease in the family."

Establishes the causal allele by segregation in the first kindred.

PMID:27242165 SUPPORT Human Clinical

"The relative amount of LAT mRNA in patient’s sorted CD4 CD45R0 T cells was within the range of three different healthy controls (Fig. 2 C), indicating that the mutation does not interfere with transcript stability."

Shows the transcript is stable, which locates the defect in the protein's adaptor function.

💊

Medical Actions

Allogeneic Hematopoietic Stem Cell Transplantation

Action: hematopoietic cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

The only reported treatment that addresses the disease rather than its complications. The index patient of the first kindred was transplanted at eight years from a fully matched heterozygous sibling; at one year the graft showed full donor chimerism with resolution of the opportunistic infections and the autoimmune cytopenias and clearance of the skin infiltrates, off immunosuppression. This is one transplanted patient with one year of follow-up, so it establishes feasibility rather than long-term outcome.

Mechanism Target:

RESTORES Impaired T Cell Activation and Proliferation — Donor-derived lymphocytes carry intact LAT and can assemble the TCR signalosome.

RESTORES Loss of LAT-Dependent Restraint on T Cell Responses — Replacing the LAT-deficient T-cell compartment removed the autoimmune cytopenias and the skin infiltrates in the transplanted patient.

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"The 1-yr follow-up demonstrated full donor chimerism, resolution of opportunistic infections and autoimmune cytopenias, and disappearance of skin infiltrates without any immunosuppressive treatment."

Reports the outcome of the one transplanted patient, covering both the infectious and the autoimmune arms.

Immunoglobulin Replacement

Action: immunoglobulin therapy Ontology label: Immunoglobulin Therapy NCIT:C62710

Platform: Protein replacement

Immunoglobulin replacement was started in the index patient at eight years once panhypogammaglobulinaemia had developed, and was given alongside antiviral therapy during his CMV and adenovirus episode, with gradual improvement. It covers the antibody deficiency and does nothing for the cellular defect.

Mechanism Target:

BYPASSES Defective T-Dependent Antibody Production — Passive antibody substitutes for the antibody the patient cannot make; it does not restore helper function.

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"At the age of 8, IgG replacement therapy was started."

Records the use of immunoglobulin replacement in the index patient.

Antiviral Therapy

Action: antiviral therapy Ontology label: Antiviral Therapy NCIT:C16119

Platform: Small molecule

Antiviral treatment was used for the CMV and adenovirus episode in the index patient, with gradual improvement in respiratory function. The oldest sibling nonetheless died of disseminated CMV while awaiting transplant, so antiviral therapy contains rather than resolves the viral susceptibility.

Mechanism Target:

MODULATES Severe cytomegalovirus infection — Suppresses viral replication without restoring the T-cell immunity that would normally control it.

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"On antiviral and IgG replacement therapy, he improved gradually, and genetic diagnosis was performed."

Records the antiviral treatment and the clinical response in the index patient.

Systemic Corticosteroid Therapy

Action: systemic corticosteroid therapy Ontology label: Systemic Corticosteroid Therapy NCIT:C122080

Agent: corticosteroid CHEBI:50858

Platform: Small molecule

Corticosteroids were used in all three siblings for the autoimmune cytopenias. They controlled them incompletely: the oldest sibling's disease was described as treatment-resistant and went on to splenectomy, and the index patient remained on steroids for severe Evans syndrome from six years until transplant.

Mechanism Target:

MODULATES Polyclonal B Cell Activation and Autoantibody Production — Broad immunosuppression dampens the autoantibody-mediated cytopenias without correcting the signalling lesion that drives them.

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"From the age of 6 yr, he was treated with steroids for severe Evans syndrome."

Records corticosteroid use for the autoimmune cytopenias in the index patient.

Splenectomy

Action: splenectomy Ontology label: Splenectomy NCIT:C15328

Platform: Surgery

Splenectomy was performed in the oldest sibling at seven years for progressive treatment-resistant autoimmune cytopenia. It did not alter the course: he died two years later of disseminated CMV while awaiting transplantation.

Mechanism Target:

MODULATES Autoimmune hemolytic anemia — Removes the principal site of antibody-coated cell destruction; it does not reduce autoantibody production.

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

Records the splenectomy, its indication, and the outcome that followed.

🔬

Diagnosis

Whole exome sequencing

The diagnosis in every reported case was molecular. Exome sequencing identified the causal homozygous variant in the first kindred and in the Iranian SCID series, with Sanger confirmation in the parents; the second pedigree was solved by homozygosity mapping followed by Sanger sequencing of LAT.

whole exome sequencing NCIT:C101295

Show evidence (2 references)

PMID:37516813 SUPPORT Human Clinical

"Moreover, all variants were confirmed in patients and their parents as a heterozygous state by Sanger sequencing."

Describes the exome-plus-Sanger route by which the LAT variant in this series was identified and confirmed in the family.

PMID:27522155 SUPPORT Human Clinical

"Homozygosity mapping was used to identify potential defective genes."

The alternative route used in the consanguineous SCID pedigree, which narrowed the search before Sanger sequencing of LAT.

Flow cytometric assessment of LAT protein expression

LAT protein was undetectable by flow cytometry with an antibody against the intracytoplasmic part of the protein in the index patient's CD4 T cells, while the heterozygous sibling showed normal levels in most cells. The assay separates affected from carrier, but note it reads the cytoplasmic region, so a truncated protein that is still made will read as absent.

immunological flow cytometry NCIT:C113003

Show evidence (1 reference)

PMID:27242165 SUPPORT Human Clinical

"The LAT protein, however, could not be detected by flow cytometry using an antibody directed against the intracytoplasmic part of LAT in CD4 T cells (Fig. 2 D) and by Western blotting of patient-derived EBV lines using a polyclonal antibody against LAT (not depicted)."

Documents the flow cytometric finding and the antibody's target, which is what the caveat in the description rests on.

📊

Prevalence

Worldwide, published cases

Cases In Literature Ultra Rare

Three kindreds have been published since the first description in 2016. No incidence or prevalence estimate exists, and none is computable from a series this size.

Show evidence (1 reference)

PMID:37516813 SUPPORT Human Clinical

"The second report of LAT deficiency in SCID patients is presented in this study."

A 2023 SCID exome series describing its own patient as the second report of LAT deficiency presenting as SCID, which places the published literature at a handful of cases.

🐁

Animal Models

Lat-null mouse

The original null model. Thymocyte development is blocked within the CD4-CD8- double-negative compartment and no mature peripheral T cells appear, while B cells are normal. It established that LAT is required for T-cell development, and its block is more complete than any human patient's.

Species

Mouse

Genotype

Lat knockout (Lat-/-)

Publication

PMID:10204488

Pathograph links

Arrest of Thymic T Cell Development partially recapitulates fidelity: moderate observes: cellular Reproduces the requirement for LAT in thymic development, and locates the checkpoint, but at a severity the human disease does not reach.

Limitations: Mice lacking LAT, and mice in which all four cytoplasmic tyrosines are replaced, have no peripheral T cells at all. Patients homozygous for an allele that removes the same four tyrosines still produce mature T cells, and in one kindred those T cells were present in normal numbers for years. A study reading peripheral T-cell numbers off this model would describe a more absolute deficit than patients have.

Divergences from the human mechanism

species mismatch qualifying

The murine developmental block is complete at the DN3 stage; the human block is partial and variable despite an allele that removes the same four phosphorylation sites. No compensating adaptor has been found to explain the difference, so the divergence is unexplained rather than attributable to a known paralogue.

Show evidence (2 references)

PMID:10204488 SUPPORT Model Organism

"Flow cytometric analysis revealed normal B cell populations but the absence of any mature peripheral T cells. Intrathymic development was blocked within the CD4- CD8- stage."

States the model's developmental block and its stage, which is the claim this link makes.

+ 1 more reference

Show evidence (1 reference)

PMID:10204488 SUPPORT Model Organism

"To probe the role of LAT in T cell development, the LAT gene was disrupted by targeting."

Establishes how the model was made.

LatY136F knock-in mouse

A knock-in replacing the PLC-gamma1 docking tyrosine and leaving the other three intact. Unlike the null, these mice pass the developmental block partially and then accumulate type 2 helper T cells, developing a polyclonal lymphoproliferative disorder, hypergammaglobulinaemia and systemic autoimmunity with nephritis. It is the model that made the immunodeficiency-with-autoimmunity combination intelligible, and it is a closer counterpart to the human CID presentation than the null is.

Species

Mouse

Genotype

Lat Y136F knock-in (homozygous)

Publication

PMID:12065840

Pathograph links

Loss of LAT-Dependent Restraint on T Cell Responses partially recapitulates fidelity: moderate observes: organism Reproduces the central paradox of the human disease: an allele that impairs receptor signalling produces lymphoproliferation and autoimmunity rather than immunological silence.

Limitations: The mouse allele removes one docking tyrosine, whereas the patients' alleles truncate the whole tail, so the model is not genotype-matched. The murine disease is also dominated by nephritis and by IgE and IgG1 hypergammaglobulinaemia, while the patients' autoimmunity is principally haematological and their immunoglobulins fall over years.

Divergences from the human mechanism

species mismatch qualifying

Systemic autoimmune nephritis with severe proteinuria dominates the murine disease; no patient developed nephritis, and the reported human autoimmunity is haematological.

Show evidence (2 references)

PMID:12065840 SUPPORT Model Organism

States the model's combination of developmental block and later lymphoproliferative autoimmunity, which is the mechanism this link attributes to it.

+ 1 more reference

Th2 Effector Skewing recapitulates fidelity: moderate observes: organism The type 2 skew is reproduced in full, and was described in the model before it was observed in patients.

Limitations: The model's type 2 response drives tissue eosinophilia and massive IgE and IgG1 plasma cell maturation; in patients it was demonstrated as constitutive IL-4 production by CD4 and gamma-delta T cells, with raised IgE recorded in only one of the three siblings.

Show evidence (1 reference)

PMID:12065839 SUPPORT Model Organism

"This exaggerated TH2 differentiation caused tissue eosinophilia and massive maturation of plasma cells secreting to immunoglobulins of the E and G1 isotypes."

Describes the type 2 phenotype of the model that this link cites it for.

Polyclonal B Cell Activation and Autoantibody Production partially recapitulates fidelity: moderate observes: organism Supplies the step from aberrant helper T cells to polyclonal, non-antigen driven B-cell activation and systemic autoimmunity.

Limitations: The autoimmune target organ differs: the model develops nephritis with IgE autoantibody deposits and severe proteinuria, whereas the patients' autoantibody disease was directed at blood cells and, in one, at ADAMTS13.

Show evidence (1 reference)

PMID:16887989 SUPPORT Model Organism

"These results show that Th2 cells developing in Lat(Y136F) mice can trigger polyclonal B cell activation and thereby lead to systemic autoimmune disease."

States the causal step from the helper T-cell abnormality to polyclonal B-cell activation and autoimmunity.

Show evidence (1 reference)

PMID:12065840 SUPPORT Model Organism

"These results identify a critical role for integrated PLC-gamma1 and Ras-Erk signaling through LAT in T cell development and homeostasis."

The model's own conclusion about what the mutated docking site does, which establishes what the model is a model of.

{ }

Source YAML

click to show

name: LAT Deficiency
creation_date: "2026-09-29T21:00:00Z"
category: Mendelian
synonyms:
- severe combined immunodeficiency due to LAT deficiency
- combined immunodeficiency due to LAT deficiency
- immunodeficiency 52
- IMD52
- SCID due to LAT deficiency
- T-B+NK+ severe combined immunodeficiency due to LAT deficiency
- LAT-related combined immunodeficiency
description: >-
  LAT deficiency is an autosomal recessive inborn error of immunity caused by
  biallelic loss-of-function variants in LAT, the transmembrane adaptor that
  ZAP-70 phosphorylates once the T-cell receptor is engaged. LAT has no catalytic
  activity of its own: its cytoplasmic tail carries four tyrosines that, when
  phosphorylated, become docking sites for PLC-gamma1, Grb2 and Gads, and through
  Gads for SLP-76. That assembly is where one receptor signal fans out into the
  calcium, Ras-ERK and transcriptional arms of T-cell activation, so losing the
  adaptor leaves the receptor intact and every branch below it unserved.

  The reported human phenotype spans two presentations that are recognisably the
  same lesion. In one pedigree the picture was typical severe combined
  immunodeficiency with absent T cells and preserved B and natural killer cells,
  and a later single patient was reported from a series of typical and atypical
  SCID without a published immunophenotype. In a consanguineous kindred with a
  truncating exon 5 variant, three siblings instead presented in the first year with combined
  immunodeficiency accompanied by severe autoimmune cytopenias, lymphadenopathy
  and splenomegaly, with T cells present at diagnosis and progressively lost; two
  died in childhood and the third was transplanted. Both presentations are
  curated here as one entry because the gene, the inheritance and the signalling
  lesion are the same, and the IUIS classification carries them as one condition.

  Two features make the disorder mechanistically interesting beyond its rarity.
  First, autoimmunity in a disease of failed T-cell activation is not a paradox in
  this pathway: mouse genetics established that LAT is itself a negative regulator
  of T-cell responses and homeostasis, and that T cells deprived of it drive
  lymphoproliferation and autoantibody production in a receptor-independent,
  quasi-mitogenic fashion. Second, human and mouse do not agree on how severe the
  developmental block is. Mice lacking LAT, or carrying all four tyrosines
  mutated, arrest at the DN3 thymocyte stage with no peripheral T cells at all,
  whereas patients lacking the same four tyrosines still produce mature, if badly
  differentiated, T cells whose receptors still mobilise calcium and activate
  NF-kappaB while ERK signalling is abolished. No compensating adaptor has been
  identified, and that residual signalling remains unexplained.
disease_term:
  preferred_term: LAT deficiency
  term:
    id: MONDO:0044721
    label: severe combined immunodeficiency due to LAT deficiency
parents:
- Primary Immunodeficiency
- Combined Immunodeficiency
classifications:
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      The IUIS 2024 update lists LAT deficiency in Table 1 (immunodeficiencies
      affecting cellular and humoral immunity), in the T-B+ severe combined
      immunodeficiency subtable. Its row carries both ends of the reported
      spectrum in one entry: typical SCID, or a combined immunodeficiency with
      adenopathy, splenomegaly, recurrent infection and autoimmunity. That the
      committee treats these as one condition is the basis for curating them as
      one dismech entry rather than splitting the SCID and CID presentations.
    evidence:
    - reference: PMID:41608114
      reference_title: "Human inborn errors of immunity: 2024 update on the classification from
        the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        LAT deficiency | LAT | AR | 617514 | Normal to low | Normal to low | High
        | Typical SCID or CID, the latter with adenopathy, splenomegaly,
        recurrent infections, autoimmunity
      explanation: >-
        The IUIS classification row for LAT, giving the gene, the autosomal
        recessive inheritance, the OMIM number, the variable T- and B-cell counts,
        and the two clinical presentations the committee treats as one condition.
references:
- reference: PMID:27242165
  title: Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function
    mutation in LAT.
- reference: PMID:27522155
  title: Mutations in linker for activation of T cells (LAT) lead to a novel form of severe
    combined immunodeficiency.
- reference: PMID:37516813
  title: "Clinical, immunological and molecular findings of 8 patients with typical and atypical
    severe combined immunodeficiency: identification of 7 novel mutations by whole exome sequencing."
- reference: PMID:27353087
  title: Human LAT mutation results in immune deficiency and autoimmunity but also raises questions
    about signaling pathways.
- reference: PMID:41608114
  title: "Human inborn errors of immunity: 2024 update on the classification from the International
    Union of Immunological Societies Expert Committee."
- reference: PMID:9489702
  title: "LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation."
- reference: PMID:26354432
  title: "The linker for activation of T cells (LAT) signaling hub: from signaling complexes to
    microclusters."
- reference: PMID:17534068
  title: Th2 lymphoproliferative disorders resulting from defective LAT signalosomes.
- reference: PMID:16102570
  title: Role of the LAT adaptor in T-cell development and Th2 differentiation.
- reference: PMID:10204488
  title: Essential role of LAT in T cell development.
- reference: PMID:12065840
  title: A LAT mutation that inhibits T cell development yet induces lymphoproliferation.
- reference: PMID:12065839
  title: Induction of T helper type 2 immunity by a point mutation in the LAT adaptor.
- reference: PMID:16887989
  title: The Th2 lymphoproliferation developing in LatY136F mutant mice triggers polyclonal B
    cell activation and systemic autoimmunity.
- reference: PMID:18209052
  title: Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently of TCR-MHC
    engagement and is insensitive to the action of Foxp3+ regulatory T cells.
- reference: PMID:19682930
  title: Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors
    that function independently of the T cell receptor.
- reference: PMID:20542732
  title: "LAT signaling pathology: an \"autoimmune\" condition without T cell self-reactivity."
- reference: PMID:26034173
  title: The Importance of IL-6 in the Development of LAT-Mediated Autoimmunity.
notes: >-
  Ultra-rare. Every claim about patients in this entry rests on three published
  kindreds: three siblings of an Israeli Arab consanguineous family homozygous for
  LAT c.268_269delGG (Keller et al., J Exp Med 2016), a pedigree with a homozygous
  frameshift abolishing LAT expression (Bacchelli et al., JACI 2017, which reports
  affected family members without giving a count in its abstract), and one patient
  homozygous for LAT p.Y207fsTer33 in an eight-patient SCID exome series (Alizadeh
  et al., Genes Immun 2023). `frequency` is
  deliberately left unset on every phenotype: with a denominator this small any
  enum value would assert a population rate that no source supports, and the
  evidence `explanation` says instead how many patients showed a finding.

  The two presentations were curated as one entry rather than split. IUIS 2024
  carries typical SCID and the CID-with-autoimmunity picture in a single row, and
  the truncating variants behind them remove the same cytoplasmic tyrosines, so
  there is no second pathomechanism to separate. Whether the difference is
  allelic, modifier-driven or an artefact of when the patients were ascertained
  cannot be answered from three kindreds; it is recorded as an open question in
  `discussions` rather than as a `has_subtypes` split.

  No GeneReviews chapter exists for LAT deficiency: `just check-genereviews`
  reports NO_CHAPTER against the committed Bookshelf index with the synonyms above
  in place. The phenotype baseline here is therefore the primary literature, and
  the great majority of it is the Keller kindred, the only report with full-text
  clinical and immunological detail.

  The umbrella entry `Severe_Combined_Immunodeficiency` carries LAT as one of its
  causal gene rows. That entry is untouched here; this one is the gene-specific
  pathomechanism it points at.

  Sibling entries in the same signalling chain are already curated: ZAP70
  deficiency (`ZAP70_Deficiency`, the kinase that phosphorylates LAT) and
  CD3gamma deficiency (`Combined_Immunodeficiency_Due_To_CD3gamma_Deficiency`,
  upstream at the receptor). Keller et al. note the clinical resemblance to ZAP70,
  ITK and LCK deficiency and what separates each: the prominent CD8 reduction in
  ZAP70 deficiency, the absent calcium signal in ITK deficiency, and the preserved
  ERK signal in LCK deficiency. The ERK-abolished, calcium-preserved pattern is
  what distinguishes LAT deficiency from those.

  LAT is expressed in mast cells, natural killer cells, megakaryocytes, platelets
  and early B cells as well as T cells, and no patient has been studied for
  platelet or mast-cell function. The one non-T lineage with human data is the NK
  compartment, whose degranulation was reduced but not absent. The gap is recorded
  in `discussions` rather than filled by inference from expression data.

  No `conforms_to` module was declared. `kb/modules/` was searched (`ls
  kb/modules/`, plus `rg -il "T cell receptor|TCR signal" kb/modules`) for a TCR
  signalling or lymphocyte activation module and none exists. If one is ever
  written, this entry, ZAP70 deficiency and CD3gamma deficiency are its first
  conformers.

  Three things the deep-research report proposed are deliberately not curated
  here, because no source ties them to this disease rather than to severe combined
  immunodeficiency in general: detection by TREC newborn screening, the standard
  SCID supportive-care package (Pneumocystis prophylaxis, irradiated and CMV-safe
  blood products, avoidance of live vaccines), and survival figures taken from
  general SCID transplant cohorts. Eosinophilia is omitted for a different reason:
  it is a feature of the LatY136F mouse, and no eosinophil count is reported for
  any patient.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All reported patients are homozygous for truncating LAT variants; the first
    kindred was born to consanguineous parents of Arab origin, and in the third
    report the parents were confirmed heterozygous by Sanger sequencing.
    Heterozygous carriers are clinically well; in the
    Keller kindred the heterozygous parents and sister had normal lymphocyte
    subsets, normal immunoglobulins and normal TCR-induced phosphorylation of
    ZAP-70, ITK and ERK, arguing against a dominant-negative effect of the
    truncated protein.
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we describe the first kindred with defective LAT signaling
      caused by a homozygous mutation in exon 5, leading to a premature stop codon
      deleting most of the cytoplasmic tail of LAT, including the critical
      tyrosine residues for signal propagation.
    explanation: >-
      Establishes homozygosity for a truncating LAT allele in the first reported
      kindred, which is the basis for the recessive classification.
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In T cells of the heterozygous parents and sister, the phosphorylation of
      ZAP70, ITK, ERK, and Ca2+ mobilization was found to be normal (not
      depicted), indicating that there is no dominant-negative effect of the
      mutation in the heterozygous situation.
    explanation: >-
      Documents normal TCR signalling in carriers, which is what makes the
      inheritance recessive rather than dominant-negative.
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Three kindreds have been published since the first description in 2016. No
    incidence or prevalence estimate exists, and none is computable from a series
    this size.
  evidence:
  - reference: PMID:37516813
    reference_title: "Clinical, immunological and molecular findings of 8 patients with typical
      and atypical severe combined immunodeficiency: identification of 7 novel mutations by whole
      exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The second report of LAT deficiency in SCID patients is presented in this
      study.
    explanation: >-
      A 2023 SCID exome series describing its own patient as the second report of
      LAT deficiency presenting as SCID, which places the published literature at
      a handful of cases.
pathophysiology:
- name: Biallelic LAT Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Homozygous truncating LAT variants. The reported alleles are the exon 5
    two-base deletion c.268_269delGG, which frameshifts at codon 89 and truncates
    the protein after 100 of 233 residues; an independent frameshift producing a
    premature stop codon with complete loss of LAT protein expression; and
    p.Y207fsTer33. All remove some or all of the cytoplasmic tyrosines. The
    c.268_269delGG transcript is present at normal levels and the truncated
    protein can be expressed from a transgene, so the lesion is in the protein's
    adaptor function rather than in transcription.
  genes:
  - preferred_term: LAT
    term:
      id: hgnc:18874
      label: LAT
    modifier: LOSS_OF_FUNCTION
  genetic_context:
    description: >-
      Germline biallelic truncating LAT alleles, homozygous in every reported
      patient, with the parents heterozygous and unaffected wherever they were
      tested.
    allelic_events:
    - FRAMESHIFT_VARIANT
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This mutation caused a deletion of guanosines 268/269 in exon 5 of LAT,
      leading to a frame shift and a premature stop codon after 303 bp (Fig. 2
      A).
    explanation: >-
      Identifies the specific frameshift allele segregating with disease in the
      first reported kindred.
  - reference: PMID:27522155
    reference_title: Mutations in linker for activation of T cells (LAT) lead to a novel form
      of severe combined immunodeficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sanger sequencing of the LAT gene showed a mutation that resulted in a
      premature stop codon and protein truncation leading to complete loss of
      function and loss of expression of LAT in the affected family members.
    explanation: >-
      Documents an independent truncating allele that abolishes LAT expression,
      establishing loss of function as the disease mechanism.
  - reference: PMID:37516813
    reference_title: "Clinical, immunological and molecular findings of 8 patients with typical
      and atypical severe combined immunodeficiency: identification of 7 novel mutations by whole
      exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutations include RAG2 (p.I273T,p.G44X), IL7R (p.F361WfsTer17), ADA
      (c.780+1G>A), JAK3 (p.Q228Ter), LIG4 (p.G428R), and LAT (p.Y207fsTer33)
    explanation: >-
      Adds a third truncating LAT allele from an independent SCID cohort, so the
      allelic spectrum is not confined to one family.
  downstream:
  - target: Loss of the LAT Cytoplasmic Phosphotyrosine Docking Sites
    causal_link_type: DIRECT
    description: >-
      Truncation removes the cytoplasmic tail carrying the phosphorylation sites,
      so no docking platform can be built regardless of upstream kinase activity.
    evidence:
    - reference: PMID:27242165
      reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
        loss-of-function mutation in LAT.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The predicted protein of 100 of the 233 aa contains an intact
        extracellular and transmembrane region but a shortened intracellular
        region, eliminating the known major phosphorylation sites Y132, Y171,
        Y191, and Y226.
      explanation: >-
        States exactly what the variant removes, which is the step from allele to
        loss of the docking sites.

- name: Loss of the LAT Cytoplasmic Phosphotyrosine Docking Sites
  biological_scale: MOLECULAR
  description: >-
    LAT works by being phosphorylated. ZAP-70, activated at the engaged receptor,
    phosphorylates the tyrosines of the LAT cytoplasmic tail; the resulting
    phosphotyrosine motifs are SH2-domain binding sites for PLC-gamma1, Grb2 and
    Gads, with Gads in turn recruiting SLP-76. Truncated LAT retains its
    extracellular and transmembrane segments and reaches the membrane but presents
    no phosphotyrosines, so the adaptor function is lost while upstream events are
    untouched: ZAP-70 phosphorylation is normal in cells expressing the mutant
    protein.
  genes:
  - preferred_term: LAT
    term:
      id: hgnc:18874
      label: LAT
    modifier: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: signaling adaptor activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0035591
      label: signaling adaptor activity
  - preferred_term: SH2 domain binding
    modifier: DECREASED
    term:
      id: GO:0042169
      label: SH2 domain binding
  evidence:
  - reference: PMID:9489702
    reference_title: "LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to
      cellular activation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that this protein is phosphorylated by ZAP-70/Syk protein tyrosine
      kinases leading to recruitment of multiple signaling molecules.
    explanation: >-
      The original identification of LAT as the ZAP-70 substrate whose
      phosphorylation recruits downstream molecules, which is the function the
      truncation removes.
  - reference: PMID:26354432
    reference_title: "The linker for activation of T cells (LAT) signaling hub: from signaling
      complexes to microclusters."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      These Tyr(P) motifs serve as binding sites for SH2 domain-containing
      proteins, including PLC-γ1, Grb2, and Gads (14–16), allowing the nucleation
      of multiple signaling complexes on LAT, which are essential for downstream
      signaling.
    explanation: >-
      Names the partners the phosphotyrosine motifs recruit, which is what the
      patients' truncated protein cannot do. Graded OTHER with quote_role
      REVIEW_SYNTHESIS because the sentence is a review's synthesis of work it did
      not perform.
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      After CD3 cross-linking, similar TCR-proximal ZAP70 phosphorylation was
      observed in LAT-deficient, LATwt-, and LATmut-expressing T cell lines (Fig.
      3 A).
    explanation: >-
      Shows the lesion is at the adaptor and not upstream of it: the kinase that
      phosphorylates LAT is activated normally in cells carrying the patient
      allele.
  downstream:
  - target: Failure of TCR Signalosome Assembly
    causal_link_type: DIRECT
    description: >-
      With no phosphotyrosines to dock on, the PLC-gamma1 and Gads-SLP-76
      complexes cannot be nucleated at the membrane.

- name: Failure of TCR Signalosome Assembly
  biological_scale: MOLECULAR
  description: >-
    The multiprotein complex that normally forms on phosphorylated LAT does not
    assemble. In cells reconstituted with the patient allele the measurable
    consequence is that PLC-gamma1 phosphorylation is absent, because PLC-gamma1
    recruitment depends on the LAT-SLP-76 signalosome. This is where a single
    receptor signal would ordinarily be diversified into the calcium and Ras-ERK
    arms, and it is the step the disease removes.
  biological_processes:
  - preferred_term: T cell receptor signaling pathway
    modifier: DECREASED
    term:
      id: GO:0050852
      label: T cell receptor signaling pathway
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In line with the literature that PLCγ1 phosphorylation depends on the
      assembly of the LAT-SLP76 signalosome (Smith-Garvin et al., 2009), PLCγ1
      phosphorylation was absent in J.CaM2.5 and J.CaM2.5-LATmut cells (Fig. 3
      A).
    explanation: >-
      Demonstrates in LAT-deficient Jurkat cells reconstituted with the patient
      allele that the signalosome-dependent step fails.
  - reference: PMID:27522155
    reference_title: Mutations in linker for activation of T cells (LAT) lead to a novel form
      of severe combined immunodeficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We also demonstrate loss of LAT expression and lack of TCR signaling
      restoration in LAT-deficient cell lines reconstituted with a synthetic LAT
      gene bearing this severe combined immunodeficiency mutation.
    explanation: >-
      An independent reconstitution experiment showing the patient allele cannot
      restore TCR signalling, which is the functional definition of this node.
  - reference: PMID:17534068
    reference_title: Th2 lymphoproliferative disorders resulting from defective LAT signalosomes.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      LAT coordinates the assembly of a multiprotein signalling complex through
      phosphotyrosine-based motifs present within its intracytoplasmic segment.
      The resulting 'LAT signalosome' links the TCR to the main intracellular
      signalling pathways that regulate T cell development and T cell function.
    explanation: >-
      States what the signalosome is and what it connects, which is the structure
      this node says fails to form.
  downstream:
  - target: Abolished TCR-Induced ERK Activation
    causal_link_type: DIRECT
    description: >-
      The Grb2-SOS arm that drives Ras-ERK is recruited through the same
      phosphotyrosine motifs.
  - target: Arrest of Thymic T Cell Development
    causal_link_type: DIRECT
    description: >-
      Pre-TCR and TCR signals that drive thymocyte maturation pass through the
      same adaptor.
  - target: Loss of LAT-Dependent Restraint on T Cell Responses
    causal_link_type: DIRECT
    description: >-
      LAT carries negative as well as positive regulatory modules, so its loss
      removes a brake at the same time as it removes the signal.
  - target: Reduced Cytotoxic Degranulation
    causal_link_type: DIRECT
    description: >-
      Signalling through LAT is beneficial, though not essential, for granule
      release by cytotoxic lymphocytes.

- name: Abolished TCR-Induced ERK Activation
  biological_scale: MOLECULAR
  description: >-
    ERK phosphorylation after receptor cross-linking is absent both in the
    patients' own T cells and in cells reconstituted with the patient allele. This
    is the branch of the cascade the human disease loses cleanly, and it is what
    distinguishes LAT deficiency from the neighbouring T-cell signalling defects:
    the calcium and NF-kappaB arms are preserved in the patients' residual T cells
    while ERK is not.
  biological_processes:
  - preferred_term: ERK1 and ERK2 cascade
    modifier: DECREASED
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite the reported nonredundant role of LAT in Ca(2+) mobilization,
      residual T cells were able to induce Ca(2+) influx and nuclear factor (NF)
      κB signaling, whereas extracellular signal-regulated kinase (ERK) signaling
      was completely abolished.
    explanation: >-
      States the selective loss of ERK signalling in patient T cells alongside
      preserved calcium and NF-kappaB responses.
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the phosphorylation of ERK was absent in LATmut-expressing CD4 T cell
      subpopulations (Fig. 4 C)
    explanation: >-
      The measurement behind the node, made directly in the patient's CD4 T cells.
  downstream:
  - target: Impaired T Cell Activation and Proliferation
    causal_link_type: DIRECT
    description: >-
      ERK output is required for the activation programme that follows receptor
      engagement.

- name: Arrest of Thymic T Cell Development
  biological_scale: CELLULAR
  description: >-
    LAT is required for the signals that carry thymocytes through development. In
    mice the requirement is absolute and the block sits at the CD25+CD44- DN3
    stage, with no peripheral T cells at all. In people the block is partial and
    variable: one pedigree had absent T cells with preserved B and NK cells, a
    T-B+NK+ SCID immunophenotype, while in the kindred with the exon 5 truncation T
    cells were present in normal numbers at presentation and fell over years. Both
    are recorded here; the species difference is taken up in `discussions`.
  biological_processes:
  - preferred_term: T cell differentiation in thymus
    modifier: DECREASED
    term:
      id: GO:0033077
      label: T cell differentiation in thymus
  cell_types:
  - preferred_term: thymocyte
    term:
      id: CL:0000893
      label: thymocyte
  evidence:
  - reference: PMID:27522155
    reference_title: Mutations in linker for activation of T cells (LAT) lead to a novel form
      of severe combined immunodeficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a pedigree affected by a severe combined immunodeficiency
      phenotype with absent T cells and normal B-cell and natural killer cell
      numbers.
    explanation: >-
      The human end of the claim: a LAT-mutant pedigree with no T cells and intact
      B and NK compartments.
  - reference: PMID:10204488
    reference_title: Essential role of LAT in T cell development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Flow cytometric analysis revealed normal B cell populations but the absence
      of any mature peripheral T cells. Intrathymic development was blocked within
      the CD4- CD8- stage.
    explanation: >-
      Establishes where in thymic development the requirement for LAT sits. Graded
      INDIRECT because the stage of the block is shown in mice and the human block
      is demonstrably less complete.
  downstream:
  - target: Severe combined immunodeficiency
    causal_link_type: DIRECT
    description: >-
      Absent thymic output produces the T-negative, B-positive, NK-positive SCID
      presentation.
  - target: Decreased total T cell count
    causal_link_type: DIRECT

- name: Loss of LAT-Dependent Restraint on T Cell Responses
  biological_scale: CELLULAR
  description: >-
    The counterintuitive arm of the disease. LAT is not only a positive conductor
    of receptor signals; it is also a negative regulator of TCR signalling and
    T-cell homeostasis, and T cells deprived of it mount self-perpetuating
    responses. Mouse genetics shows this directly: deleting LAT from post-thymic
    CD4 T cells, or replacing the PLC-gamma1 docking tyrosine, produces a
    lymphoproliferative disorder with excessive cytokine production and
    autoantibodies rather than a quiescent immunodeficiency, and the expansion is
    receptor-independent rather than driven by self-reactive clones. The patients
    show the corresponding clinical picture, with lymphoproliferation and severe
    autoimmune cytopenias from the first year of life.
  biological_processes:
  - preferred_term: T cell homeostasis
    modifier: DECREASED
    term:
      id: GO:0043029
      label: T cell homeostasis
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  evidence:
  - reference: PMID:19682930
    reference_title: Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic
      effectors that function independently of the T cell receptor.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      The fact that such LAT-independent signals result in lymphoproliferative
      disorders with excessive cytokine production demonstrates that LAT
      constitutes a key negative regulator of the triggering module and of the
      LAT-independent branches of the TCR signaling cassette.
    explanation: >-
      States the negative-regulator role that makes autoimmunity a predicted
      rather than paradoxical consequence of losing LAT. INDIRECT because the
      demonstration is in conditionally LAT-deleted mouse T cells.
  - reference: PMID:18209052
    reference_title: Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently
      of TCR-MHC engagement and is insensitive to the action of Foxp3+ regulatory T cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      These results argue against a scenario where the Lat(Y136F) pathology is
      primarily due to a lack of functional Foxp3(+) regulatory T cells and
      suggest that a defect intrinsic to Lat(Y136F) CD4 T cells leads to a state
      of TCR-independent hyperactivity.
    explanation: >-
      Locates the defect inside the T cell rather than in regulatory T-cell
      control, which is what makes this a loss of intrinsic restraint.
  - reference: PMID:20542732
    reference_title: "LAT signaling pathology: an \"autoimmune\" condition without T cell self-reactivity."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In the absence of LAT, antigen-specific T cells give rise to
      self-perpetuating pro-inflammatory responses and induce the production of
      autoantibodies independently of TCR engagement.
    explanation: >-
      A review's synthesis of the mouse work, stating the mechanism by which loss
      of a positive signalling adaptor yields immune pathology.
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three patients presented with recurrent infection, lymphoproliferation,
      and life-threatening autoimmune disease since early infancy.
    explanation: >-
      The human counterpart: immunodeficiency and immune dysregulation together in
      every patient of the kindred.
  downstream:
  - target: Polyclonal Lymphoproliferation
    causal_link_type: DIRECT
  - target: Th2 Effector Skewing
    causal_link_type: DIRECT
    description: >-
      Weak or absent TCR signalling through LAT biases effector differentiation
      toward type 2 cytokine production.
  - target: Peripheral Gamma-Delta T Cell Expansion
    causal_link_type: DIRECT

- name: Impaired T Cell Activation and Proliferation
  biological_scale: CELLULAR
  description: >-
    The T cells that do reach the periphery cannot be activated. Receptor
    cross-linking induces only reduced levels of CD69, ICOS and CD25, and
    co-stimulation through CD28 does not rescue it; proliferation to anti-CD3 and
    anti-CD3/CD28 is abrogated and to phytohaemagglutinin strongly reduced.
  biological_processes:
  - preferred_term: T cell activation
    modifier: DECREASED
    term:
      id: GO:0042110
      label: T cell activation
  - preferred_term: T cell proliferation
    modifier: DECREASED
    term:
      id: GO:0042098
      label: T cell proliferation
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anti-CD3 stimulation for 20 h induced only reduced levels of CD69,
      inducible T cell co-stimulator (ICOS), and CD25 in LATmut T cells, which
      could not be increased by the addition of anti-CD28 (Fig. 6 B).
    explanation: >-
      Measures the activation failure in the patient's own T cells and shows
      co-stimulation does not compensate.
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similarly, in vitro proliferation of CD4 T cells (Fig. 6 C) and CD8 T cells
      (not depicted) after stimulation with anti-CD3, anti-CD3/anti-CD28 was
      abrogated and strongly reduced after PHA compared with the control.
    explanation: >-
      The proliferation half of the node, in patient cells against day controls.
  downstream:
  - target: Susceptibility to Severe and Opportunistic Infection
    causal_link_type: DIRECT
  - target: Defective T-Dependent Antibody Production
    causal_link_type: DIRECT
  - target: Decreased anti-CD3/28-induced T-cell proliferation
    causal_link_type: DIRECT
  - target: Decreased T cell activation
    causal_link_type: DIRECT

- name: Reduced Cytotoxic Degranulation
  biological_scale: CELLULAR
  description: >-
    Granule release by the patients' cytotoxic lymphocytes is reduced but not
    absent: CD107a upregulation on CD8 T cells after bead stimulation and on NK
    cells after exposure to K562 targets was below control, and NK-cell
    cytotoxicity in the oldest sibling was diminished. The partial rather than
    complete defect matches mouse work showing LAT is beneficial but not essential
    for degranulation, and this is the only non-T lineage in which patients have
    been tested.
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: >-
      This might reflect previous results from mice that signaling via LAT is not
      essential but beneficial for the process of degranulation
    explanation: >-
      The sentence in which the reporting authors attribute the partial rather
      than complete degranulation defect to the mouse result. Graded
      MODEL_ORGANISM because the evidence it describes is murine, with
      quote_role BACKGROUND because the citing paper is restating it rather than
      reporting it.
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, the degranulation of LATmut CTLs after stimulation with
      anti-CD3/anti-CD28 beads (Fig. 6 D) and of patient-derived NK cells after
      stimulation with the K562 cell line was reduced (Fig. 6 E), although not
      absent.
    explanation: >-
      Reports both degranulation measurements and their partial character, which
      is what this node claims.
  downstream:
  - target: Decreased CD8+ T cell degranulation
    causal_link_type: DIRECT
  - target: Decreased natural killer cell degranulation
    causal_link_type: DIRECT
  - target: Susceptibility to Severe and Opportunistic Infection
    causal_link_type: DIRECT
    description: >-
      Reduced cytotoxic output contributes to the failure to clear virally
      infected cells, alongside the activation defect.

- name: Th2 Effector Skewing
  biological_scale: CELLULAR
  description: >-
    A high proportion of the patients' memory CD4 T cells produce interleukin-4
    without stimulation, and the same excess of spontaneous IL-4 producers appears
    in their expanded gamma-delta compartment. The corresponding mouse mutant
    accumulates helper T cells chronically producing type 2 cytokines, with tissue
    eosinophilia and massive IgE and IgG1 plasma cell maturation, so the skew is a
    reproducible consequence of weakened signalling through this adaptor rather
    than an incidental finding in one patient.
  biological_processes:
  - preferred_term: T-helper 2 cell differentiation
    modifier: INCREASED
    term:
      id: GO:0045064
      label: T-helper 2 cell differentiation
  cell_types:
  - preferred_term: T-helper 2 cell
    term:
      id: CL:0000546
      label: T-helper 2 cell
    modifier: INCREASED
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In accordance with LAT-deficient mice, a high percentage of
      LATmut-expressing CD4 T cells constitutively produced IL-4, implying an
      expansion of the T helper type 2 cell (Th2) phenotype (Fig. 6 A).
    explanation: >-
      The human observation of constitutive IL-4 production by the patient's CD4
      T cells.
  - reference: PMID:12065839
    reference_title: Induction of T helper type 2 immunity by a point mutation in the LAT adaptor.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      However, later they accumulated polyclonal helper T (TH) cells that
      chronically produced type 2 cytokines in large amounts.
    explanation: >-
      The mouse counterpart of the same skew, cited as corroboration rather than
      as evidence about patients.
  downstream:
  - target: Polyclonal B Cell Activation and Autoantibody Production
    causal_link_type: DIRECT
    description: >-
      Type 2 helper output drives the B-cell activation arm.
  - target: Increased circulating IgE concentration
    causal_link_type: DIRECT

- name: Peripheral Gamma-Delta T Cell Expansion
  biological_scale: CELLULAR
  description: >-
    Every patient in the Keller kindred had a striking excess of circulating
    gamma-delta T cells, up to 80% of the T-cell pool in one, and the expanded
    population was skewed away from the normally dominant Vdelta2 subset toward
    Vdelta1 and Vdelta3. Mouse mutants carrying targeted mutations of the three
    distal tyrosines expand gamma-delta T cells in spleen and lymph node, which is
    the closest model counterpart; complete LAT loss in mice instead abolishes
    peripheral gamma-delta T cells altogether.
  biological_processes:
  - preferred_term: gamma-delta T cell proliferation
    modifier: INCREASED
    term:
      id: GO:0046630
      label: gamma-delta T cell proliferation
  cell_types:
  - preferred_term: gamma-delta T cell
    term:
      id: CL:0000798
      label: gamma-delta T cell
    modifier: INCREASED
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A common finding in all patients was the remarkable increase of γδ T cells.
    explanation: >-
      States the finding and that it was present in all three patients of the
      kindred.
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unlike in healthy individuals, the most abundant circulating Vδ2-positive
      γδ T cell population was nearly absent in patient 2 (Fig. 7 A), and in line
      with this finding, Vγ9-positive cells were <5% (not depicted).
    explanation: >-
      Records the repertoire skew within the expanded compartment, which is what
      makes this more than a numerical increase.
  downstream:
  - target: Increased gamma-delta T cell proportion
    causal_link_type: DIRECT

- name: Polyclonal Lymphoproliferation
  biological_scale: ORGANISM
  description: >-
    Lymphadenopathy and splenomegaly were present in all three patients of the
    first kindred from infancy, one required splenectomy, and lymph node histology
    showed distorted architecture with poorly formed follicles and no Bcl6-positive
    germinal centres.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The histological examination of lymph nodes from patients 1 and 2 showed
      distorted architecture with poorly formed follicles (not depicted).
    explanation: >-
      The tissue-level correlate of the lymphoproliferation, in two of the three
      patients.
  - reference: PMID:12065840
    reference_title: A LAT mutation that inhibits T cell development yet induces lymphoproliferation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Mice homozygous for a single tyrosine mutation in LAT (linker for
      activation of T cells) exhibited an early block in T cell maturation but
      later developed a polyclonal lymphoproliferative disorder and signs of
      autoimmune disease.
    explanation: >-
      Establishes in the model that the same lesion produces a developmental block
      and a later lymphoproliferative disorder, which is the combination the
      patients show.
  downstream:
  - target: Lymphadenopathy
    causal_link_type: DIRECT
  - target: Splenomegaly
    causal_link_type: DIRECT
  - target: Hepatomegaly
    causal_link_type: DIRECT
  - target: Absence of lymph node germinal center
    causal_link_type: DIRECT
  - target: Dermal Lymphocytic Infiltration
    causal_link_type: DIRECT
  - target: Progressive Immune Collapse
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The two older patients' lymphocyte counts and immunoglobulins fell over
      years, after a period of normal values, in the setting of sustained
      dysregulation and repeated infection. The authors read the decline as
      secondary to that combination rather than to a defined mechanism, so the
      link is recorded with unknown intermediates.
    intermediate_mechanisms:
    - Sustained immune dysregulation and repeated infection, with no identified intermediate
      mechanism

- name: Dermal Lymphocytic Infiltration
  biological_scale: TISSUE
  description: >-
    Persistent red to purple oedematous skin nodules on the face and forearms were
    present in the two older siblings. Biopsy showed extensive lymphoid infiltration
    of the dermis, sparing the epidermis, mainly by CD8 T cells, with in situ
    hybridisation for EBV-encoded RNA negative and no fungi or acid-fast bacteria,
    so the lesions are infiltrative rather than infectious.
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The skin biopsies showed extensive lymphoid infiltration of the dermis but
      not the epidermis, mainly by CD8 T cells.
    explanation: >-
      The histological basis for this node and for its restriction to the dermis.
  downstream:
  - target: Skin nodule
    causal_link_type: DIRECT

- name: Polyclonal B Cell Activation and Autoantibody Production
  biological_scale: CELLULAR
  description: >-
    Autoantibody-mediated disease dominates the clinical picture of the CID
    presentation: Coombs-positive autoimmune haemolytic anaemia, immune
    thrombocytopenia and autoimmune neutropenia, and in the youngest sibling a
    fatal anti-ADAMTS13-positive thrombotic microangiopathy. The mouse tyrosine
    mutant supplies the mechanism, in which aberrant helper T cells drive
    polyclonal, antigen-independent B-cell activation and systemic autoimmunity.
  biological_processes:
  - preferred_term: B cell activation
    modifier: INCREASED
    term:
      id: GO:0042113
      label: B cell activation
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:16887989
    reference_title: The Th2 lymphoproliferation developing in LatY136F mutant mice triggers
      polyclonal B cell activation and systemic autoimmunity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      In Lat(Y136F) mice, B cell activation was polyclonal and not Ag-driven
      because the increase in serum IgG1 and IgE concentrations involved Abs and
      autoantibodies with different specificities equally.
    explanation: >-
      Supplies the polyclonal, antigen-independent character of the B-cell
      activation. INDIRECT because it is established in the mouse tyrosine mutant
      rather than in patients.
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 1 presented at the age of 5 mo with the first severe episode of
      Coombs-positive autoimmune hemolytic anemia and immune-mediated
      thrombocytopenia, lymphadenopathy, and massive splenomegaly.
    explanation: >-
      The human autoantibody-mediated disease this node stands for, with its age
      of onset.
  downstream:
  - target: Autoimmune hemolytic anemia
    causal_link_type: DIRECT
  - target: Autoimmune thrombocytopenia
    causal_link_type: DIRECT
  - target: Autoimmune neutropenia
    causal_link_type: DIRECT
  - target: Anti-ADAMTS13 antibody positivity
    causal_link_type: DIRECT
    description: >-
      The ADAMTS13 autoantibody is one of the autoantibodies this node
      produces, and it is what drives the thrombotic microangiopathy below.

- name: Defective T-Dependent Antibody Production
  biological_scale: CELLULAR
  description: >-
    Helper function fails along with the rest of T-cell activation. Serum
    immunoglobulins were normal or high in early childhood in the CID kindred and
    then fell: one patient developed hypogammaglobulinaemia with partially reduced
    specific antibody responses at four years, and another progressed to
    panhypogammaglobulinaemia requiring replacement. Class-switched and IgM memory
    B cells were strongly reduced and lymph node germinal centres were absent.
  biological_processes:
  - preferred_term: immunoglobulin production
    modifier: DECREASED
    term:
      id: GO:0002377
      label: immunoglobulin production
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 4 yr, he developed hypogammaglobulinemia with partially
      reduced specific antibody responses.
    explanation: >-
      Records the loss of antibody production and of specific responses in a
      patient whose immunoglobulins had previously been normal.
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Absolute and relative numbers of B cells were reduced, and a relative
      increase of transitional B cells was observed, whereas class-switched and
      IgM memory B cells were strongly decreased.
    explanation: >-
      The B-cell compartment correlate of failed T-dependent help.
  downstream:
  - target: Panhypogammaglobulinemia
    causal_link_type: DIRECT
  - target: Decreased class-switched memory B cell proportion
    causal_link_type: DIRECT

- name: Susceptibility to Severe and Opportunistic Infection
  biological_scale: ORGANISM
  description: >-
    Without functional T-cell immunity the patients cannot control common or
    opportunistic pathogens. The reported infections are recurrent pneumonia from
    infancy, cytomegalovirus viraemia in all three siblings of the first kindred,
    adenovirus, varicella, Candida pneumonia, congenital toxoplasmosis,
    Epstein-Barr viraemia, and in the youngest sibling urinary infections and
    gastroenteritis. Two of the three died of infection or its consequences, one of
    disseminated CMV while awaiting transplant.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For progressive treatment–resistant autoimmune cytopenia, he was
      splenectomized at the age of 7 yr, but at age 9, awaiting hematopoietic stem
      cell transplantation, he died because of disseminated CMV infection with
      pulmonary involvement.
    explanation: >-
      The clinical consequence of the infection susceptibility, including its
      fatal outcome in one patient.
  downstream:
  - target: Recurrent pneumonia
    causal_link_type: DIRECT
  - target: Severe cytomegalovirus infection
    causal_link_type: DIRECT
  - target: Opportunistic infection
    causal_link_type: DIRECT
  - target: Recurrent urinary tract infections
    causal_link_type: DIRECT

- name: Progressive Immune Collapse
  biological_scale: ORGANISM
  description: >-
    A second phase of the CID presentation, and what makes the disease progressive
    rather than static. Both older siblings began with normal lymphocyte counts and
    immunoglobulins, then lost T cells, B cells and immunoglobulin over several
    years while autoimmunity and infection continued. The youngest sibling died at
    two years, before reaching this phase.
  biological_processes:
  - preferred_term: T cell homeostasis
    modifier: DECREASED
    term:
      id: GO:0043029
      label: T cell homeostasis
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During the progression of the disease, the immune systems of the two older
      patients seemed to collapse, lymphocytopenia and hypogammaglobulinemia
      developed, and opportunistic as well as other infections occurred.
    explanation: >-
      States the progressive attrition directly, and that it followed a period of
      normal counts.
  downstream:
  - target: Decreased total lymphocyte count
    causal_link_type: DIRECT
  - target: Decreased total B cell count
    causal_link_type: DIRECT
  - target: Decreased total CD4+ T cell count
    causal_link_type: DIRECT
  - target: Panhypogammaglobulinemia
    causal_link_type: DIRECT
phenotypes:
- category: Immunological
  name: Severe combined immunodeficiency
  description: >-
    The severe end of the reported spectrum: absent circulating T cells with
    preserved B and natural killer cells, a T-B+NK+ SCID immunophenotype. This is
    how the Bacchelli pedigree presented. The Keller kindred instead had T cells
    present at diagnosis and a combined immunodeficiency picture, and the later
    Iranian patient is reported in a typical-and-atypical SCID series whose
    abstract gives no immunophenotype for him.
  phenotype_term:
    preferred_term: Severe combined immunodeficiency
    term:
      id: HP:0004430
      label: Severe combined immunodeficiency
  evidence:
  - reference: PMID:27522155
    reference_title: Mutations in linker for activation of T cells (LAT) lead to a novel form
      of severe combined immunodeficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a pedigree affected by a severe combined immunodeficiency
      phenotype with absent T cells and normal B-cell and natural killer cell
      numbers. A novel homozygous frameshift mutation in the gene encoding for LAT
      was identified in this kindred.
    explanation: >-
      Names the SCID phenotype and its immunophenotype in a LAT-mutant pedigree.
- category: Laboratory
  name: Decreased total T cell count
  description: >-
    T-cell numbers range from absent at presentation, in the SCID pedigree, to
    normal at presentation and progressively reduced thereafter, in the CID
    kindred. The IUIS table records the T-cell column for LAT deficiency as normal
    to low for this reason.
  phenotype_term:
    preferred_term: Decreased total T cell count
    term:
      id: HP:0005403
      label: Decreased total T cell count
  evidence:
  - reference: PMID:41608114
    reference_title: "Human inborn errors of immunity: 2024 update on the classification from
      the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      LAT deficiency | LAT | AR | 617514 | Normal to low | Normal to low | High
      | Typical SCID or CID, the latter with adenopathy, splenomegaly,
      recurrent infections, autoimmunity
    explanation: >-
      The IUIS row records the T-cell count for LAT deficiency as normal to low,
      which is the variability this phenotype describes.
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unlike in the mouse counterpart, reduced numbers of T cells were present in
      the patients.
    explanation: >-
      States the reduced but non-zero T-cell counts of the CID kindred.
- category: Laboratory
  name: Decreased total CD4+ T cell count
  description: >-
    CD4 T cells were the most severely affected subset in the CID kindred, with the
    naive CD4 compartment hit hardest and recent thymic emigrants markedly reduced.
  phenotype_term:
    preferred_term: Decreased total CD4+ T cell count
    term:
      id: HP:5210418
      label: Decreased total CD4+ T cell count
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CD4 T cells were severely decreased, especially affecting the naive CD4 T
      cell subpopulation, whereas the percentage of regulatory T cells and
      circulating T follicular helper cell populations showed minor changes (Table
      2).
    explanation: >-
      Records the CD4 deficit and locates it in the naive compartment.
- category: Laboratory
  name: Increased gamma-delta T cell proportion
  description: >-
    A striking and consistent finding, present in all three patients of the CID
    kindred and reaching 80% of the T-cell pool in one. The heterozygous sister had
    nearly 10% gamma-delta T cells, above the normal range but far below the
    patients.
  phenotype_term:
    preferred_term: Increased gamma-delta T cell proportion
    term:
      id: HP:0500270
      label: Increased gamma-delta T cell proportion
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An increased number of γδ T cells (up to 80% of T cells) was noted on
      several occasions.
    explanation: >-
      Quantifies the gamma-delta excess in one of the patients.
- category: Laboratory
  name: Decreased T cell activation
  description: >-
    Upregulation of the activation markers CD69, CD25 and ICOS after receptor
    cross-linking is reduced and is not rescued by CD28 co-stimulation.
  phenotype_term:
    preferred_term: Decreased T cell activation
    term:
      id: HP:0005419
      label: Decreased T cell activation
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anti-CD3 stimulation for 20 h induced only reduced levels of CD69,
      inducible T cell co-stimulator (ICOS), and CD25 in LATmut T cells, which
      could not be increased by the addition of anti-CD28 (Fig. 6 B).
    explanation: >-
      The activation-marker measurement in the patient's own T cells that this
      phenotype names.
- category: Laboratory
  name: Decreased anti-CD3/28-induced T-cell proliferation
  description: >-
    Proliferation to anti-CD3 and anti-CD3/anti-CD28 was abrogated in both CD4 and
    CD8 T cells, and strongly reduced to phytohaemagglutinin.
  phenotype_term:
    preferred_term: Decreased anti-CD3/28-induced T-cell proliferation
    term:
      id: HP:0031382
      label: Decreased anti-CD3/28-induced T-cell proliferation
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similarly, in vitro proliferation of CD4 T cells (Fig. 6 C) and CD8 T cells
      (not depicted) after stimulation with anti-CD3, anti-CD3/anti-CD28 was
      abrogated and strongly reduced after PHA compared with the control.
    explanation: >-
      The measurement this phenotype names, made in patient cells.
- category: Laboratory
  name: Decreased CD8+ T cell degranulation
  description: >-
    CD107a upregulation on the patient's CD8 T cells after anti-CD3/anti-CD28 bead
    stimulation was reduced, though not absent.
  phenotype_term:
    preferred_term: Decreased CD8+ T cell degranulation
    term:
      id: HP:0025835
      label: Decreased CD8+ T cell degranulation
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, the degranulation of LATmut CTLs after stimulation with
      anti-CD3/anti-CD28 beads (Fig. 6 D) and of patient-derived NK cells after
      stimulation with the K562 cell line was reduced (Fig. 6 E), although not
      absent.
    explanation: >-
      Reports the cytotoxic T-lymphocyte degranulation defect directly.
- category: Laboratory
  name: Decreased natural killer cell degranulation
  description: >-
    NK-cell degranulation against K562 targets was reduced in the index patient and
    NK cytotoxicity was diminished in his older brother. This is the only non-T
    lineage in which LAT-deficient patients have been functionally assessed.
  phenotype_term:
    preferred_term: Decreased natural killer cell degranulation
    term:
      id: HP:0025807
      label: Decreased natural killer cell degranulation
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Accordingly, NK cells of patient 1 showed diminished cytotoxicity compared
      with day controls (not depicted).
    explanation: >-
      Records the NK functional defect in a second patient, alongside the
      degranulation assay in the index patient.
- category: Immunological
  name: Recurrent pneumonia
  description: >-
    Recurrent respiratory tract infection from the first year of life in all three
    patients of the CID kindred, progressing to chronic lung disease in two.
  phenotype_term:
    preferred_term: Recurrent pneumonia
    term:
      id: HP:0006532
      label: Recurrent pneumonia
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      From 1 yr of age, he suffered from recurrent respiratory tract infections,
      which progressed to chronic lung disease with bronchiectasis.
    explanation: >-
      Documents the recurrent respiratory infection and the structural lung damage
      it produced.
  sequelae:
  - target: Bronchiectasis
    description: >-
      Repeated lower respiratory infection produced permanent airway dilatation in
      two of the three patients.
- category: Respiratory
  name: Bronchiectasis
  description: >-
    Chronic lung disease with bronchiectasis developed in the two older siblings of
    the CID kindred as a consequence of repeated respiratory infection.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had additionally suffered from chronic lung disease with bronchiectasis
      and disseminated purple edematous skin lesions on his face and arms.
    explanation: >-
      Names bronchiectasis in the oldest sibling.
- category: Immunological
  name: Severe cytomegalovirus infection
  description: >-
    Cytomegalovirus viraemia occurred in all three siblings of the CID kindred and
    disseminated fatally in one. It is the single infection most prominent in the
    reported course.
  phenotype_term:
    preferred_term: Severe cytomegalovirus infection
    term:
      id: HP:0031692
      label: Severe cytomegalovirus infection
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At age 7 yr, varicella infection was diagnosed, and shortly after, he
      developed CMV and adenoviral infection with severe progressive deterioration
      of respiratory function.
    explanation: >-
      Records severe CMV disease with respiratory deterioration in the index
      patient.
- category: Immunological
  name: Opportunistic infection
  description: >-
    Beyond CMV, the reported opportunistic infections include Candida pneumonia,
    adenovirus, and congenital toxoplasmosis with resulting leukoencephalopathy and
    cerebral palsy in the index patient.
  phenotype_term:
    preferred_term: Opportunistic infection
    term:
      id: HP:0031690
      label: Opportunistic infection
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During the progression of the disease, the immune systems of the two older
      patients seemed to collapse, lymphocytopenia and hypogammaglobulinemia
      developed, and opportunistic as well as other infections occurred.
    explanation: >-
      States that opportunistic infection was part of the clinical course.
- category: Renal
  name: Recurrent urinary tract infections
  description: >-
    Repeated urinary infection was part of the infectious picture in the youngest
    sibling, whose presentation at ten months also included pneumonia and
    gastroenteritis. A single gastroenteritis episode is recorded as well, but
    there is no HPO term for non-recurrent gastroenteritis and the source does not
    say it recurred, so it is described in the upstream mechanism node rather than
    bound to the recurrent term.
  phenotype_term:
    preferred_term: Recurrent urinary tract infections
    term:
      id: HP:0000010
      label: Recurrent urinary tract infections
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent pneumonia, urinary infections, gastroenteritis, CMV viremia
    explanation: >-
      The infection row of the clinical summary table for the third patient, whose
      plural "urinary infections" is what supports the recurrent binding.
- category: Hematological
  name: Autoimmune hemolytic anemia
  description: >-
    Coombs-positive autoimmune haemolytic anaemia in two of the three siblings of
    the CID kindred, presenting as early as five months of age and in one case
    resistant to treatment.
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 1 presented at the age of 5 mo with the first severe episode of
      Coombs-positive autoimmune hemolytic anemia and immune-mediated
      thrombocytopenia, lymphadenopathy, and massive splenomegaly.
    explanation: >-
      Names the Coombs-positive haemolytic anaemia and its age of onset.
- category: Hematological
  name: Autoimmune thrombocytopenia
  description: >-
    Immune-mediated thrombocytopenia accompanied the haemolytic anaemia in two
    siblings, giving an Evans syndrome picture in the index patient.
  phenotype_term:
    preferred_term: Autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autoimmunity | Coombs+ AIHA, ITP, autoimmune neutropenia | Coombs+ AIHA,
      ITP | Anti-ADAMTS13+ microangiopathic hemolytic anemia
    explanation: >-
      The autoimmunity row of the clinical summary table, recording immune
      thrombocytopenia in the two older siblings.
- category: Hematological
  name: Autoimmune neutropenia
  description: >-
    Autoimmune neutropenia was recorded in the oldest sibling alongside the other
    two cytopenias.
  phenotype_term:
    preferred_term: Autoimmune neutropenia
    term:
      id: HP:0001904
      label: Autoimmune neutropenia
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autoimmunity | Coombs+ AIHA, ITP, autoimmune neutropenia | Coombs+ AIHA,
      ITP | Anti-ADAMTS13+ microangiopathic hemolytic anemia
    explanation: >-
      The autoimmunity row of the clinical summary table, which records autoimmune
      neutropenia in the first patient.
- category: Hematological
  name: Microangiopathic hemolytic anemia
  description: >-
    The youngest sibling died at two years of anti-ADAMTS13-positive
    microangiopathic haemolytic anaemia with thrombocytopenia, a thrombotic
    thrombocytopenic purpura picture rather than the autoimmune cytopenias of her
    brothers.
  phenotype_term:
    preferred_term: Microangiopathic hemolytic anemia
    term:
      id: HP:0001937
      label: Microangiopathic hemolytic anemia
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 2 yr, she died of anti-ADAMTS13–positive microangiopathic
      hemolytic anemia and thrombocytopenia.
    explanation: >-
      Names the microangiopathic haemolysis and its fatal outcome.
- category: Laboratory
  name: Anti-ADAMTS13 antibody positivity
  description: >-
    An acquired ADAMTS13 autoantibody was the basis of the fatal thrombotic
    microangiopathy in the youngest sibling.
  phenotype_term:
    preferred_term: Anti-ADAMTS13 antibody positivity
    term:
      id: HP:6000462
      label: Anti-ADAMTS13 antibody positivity
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 2 yr, she died of anti-ADAMTS13–positive microangiopathic
      hemolytic anemia and thrombocytopenia.
    explanation: >-
      Records the ADAMTS13 autoantibody directly.
  sequelae:
  - target: Microangiopathic hemolytic anemia
    description: >-
      The acquired ADAMTS13 autoantibody is what produced the thrombotic
      microangiopathy, so the causation runs from the antibody to the
      haemolysis and not the other way round.
    causal_link_type: DIRECT
- category: Immunological
  name: Lymphadenopathy
  description: >-
    Lymphadenopathy was present in all three siblings of the CID kindred from
    infancy.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymphoproliferation | Lymphadenopathy, splenomegaly | Lymphadenopathy,
      splenomegaly | Lymphadenopathy, splenomegaly
    explanation: >-
      The lymphoproliferation row of the clinical summary table, recording
      lymphadenopathy in each of the three patients.
- category: Hematological
  name: Splenomegaly
  description: >-
    Splenomegaly accompanied the lymphadenopathy in all three siblings and was
    massive in the oldest, who was splenectomised at seven years for refractory
    autoimmune cytopenia.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Like his brother, he suffered from hepatosplenomegaly, lymphadenopathy, and
      persistent red edematous nodules on his forearms.
    explanation: >-
      Records splenic enlargement, here as hepatosplenomegaly, in the index
      patient.
- category: Gastrointestinal
  name: Hepatomegaly
  description: >-
    Liver enlargement accompanied the splenomegaly in the index patient, recorded
    as hepatosplenomegaly.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Like his brother, he suffered from hepatosplenomegaly, lymphadenopathy, and
      persistent red edematous nodules on his forearms.
    explanation: >-
      Records hepatosplenomegaly in the index patient, of which liver enlargement
      is the hepatic component.
- category: Dermatological
  name: Skin nodule
  description: >-
    Persistent red to purple oedematous nodules on the forearms and face in the two
    older siblings, biopsied and shown to be dense dermal lymphoid infiltrates
    rather than an infectious eruption.
  phenotype_term:
    preferred_term: Skin nodule
    term:
      id: HP:0200036
      label: Skin nodule
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Like his brother, he suffered from hepatosplenomegaly, lymphadenopathy, and
      persistent red edematous nodules on his forearms.
    explanation: >-
      Names the skin nodules and their persistence in the index patient.
- category: Histopathological
  name: Absence of lymph node germinal center
  description: >-
    Lymph node architecture was distorted with poorly formed follicles; CD20
    positive aggregates were associated with CD21 positive follicular dendritic
    cells, but Bcl6 positive germinal centres were absent.
  phenotype_term:
    preferred_term: Absence of lymph node germinal center
    term:
      id: HP:0002849
      label: Absence of lymph node germinal center
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aggregates of small, CD20-positive cells were associated with CD21-positive
      follicular dendritic cells, but Bcl6-positive germinal centers were absent.
    explanation: >-
      The histological finding this phenotype names, in lymph nodes from two
      patients.
- category: Laboratory
  name: Panhypogammaglobulinemia
  description: >-
    Immunoglobulins fell from normal or elevated values in early childhood to
    panhypogammaglobulinaemia requiring replacement therapy by eight years in the
    index patient.
  phenotype_term:
    preferred_term: Panhypogammaglobulinemia
    term:
      id: HP:0003139
      label: Panhypogammaglobulinemia
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ig levels dropped from hypergammaglobulinemia with normal IgA and IgM to
      panhypogammaglobulinemia.
    explanation: >-
      Documents the fall to panhypogammaglobulinaemia in the index patient.
- category: Laboratory
  name: Increased circulating IgE concentration
  description: >-
    The youngest sibling had hypergammaglobulinaemia with elevated IgE, in keeping
    with the type 2 skew seen in the T-cell compartment and in the corresponding
    mouse mutants.
  phenotype_term:
    preferred_term: Increased circulating IgE concentration
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The immunological evaluation of patient 3 at the age of 2 yr was remarkable
      for hypergammaglobulinemia and elevated IgE.
    explanation: >-
      Records the raised IgE in the third patient.
- category: Laboratory
  name: Decreased class-switched memory B cell proportion
  description: >-
    Class-switched and IgM memory B cells were strongly reduced in the index
    patient, with a relative increase in transitional B cells.
  phenotype_term:
    preferred_term: Decreased class-switched memory B cell proportion
    term:
      id: HP:0030388
      label: Decreased class-switched memory B cell proportion
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Absolute and relative numbers of B cells were reduced, and a relative
      increase of transitional B cells was observed, whereas class-switched and
      IgM memory B cells were strongly decreased.
    explanation: >-
      Names the class-switched memory B-cell deficit.
- category: Laboratory
  name: Decreased total lymphocyte count
  description: >-
    Progressive lymphopenia developed in both older siblings after years of normal
    counts, reaching panlymphopenia in the index patient by eight years.
  phenotype_term:
    preferred_term: Decreased total lymphocyte count
    term:
      id: HP:0001888
      label: Decreased total lymphocyte count
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 8 yr, patient 2 had developed panlymphopenia leading to
      strongly reduced absolute counts of all B and CD4 T cell subpopulations.
    explanation: >-
      Records the panlymphopenia and the subsets it affected.
- category: Laboratory
  name: Decreased total B cell count
  description: >-
    B-cell numbers were normal at presentation and fell with the rest of the
    lymphocyte compartment; the authors read this as secondary to progressive
    immune dysregulation rather than as a primary B-cell defect.
  phenotype_term:
    preferred_term: Decreased total B cell count
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given the initial records of normal numbers of B and NK cells in patient 2
      and normal Ig levels in all siblings at a younger age, the latter changes
      are likely to be secondary to progressive immune dysregulation.
    explanation: >-
      Records both the fall in B cells and the authors' reading of it as a
      secondary change.
genetic:
- name: LAT
  gene_term:
    preferred_term: LAT
    term:
      id: hgnc:18874
      label: LAT
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    LAT encodes the linker for activation of T cells, a transmembrane adaptor with
    a short extracellular segment, a transmembrane domain and a long cytoplasmic
    tail carrying the tyrosines Y132, Y171, Y191 and Y226. All reported
    disease-causing alleles are homozygous truncating variants that remove some or
    all of those tyrosines: c.268_269delGG in exon 5, an independent frameshift
    abolishing protein expression, and p.Y207fsTer33. The c.268_269delGG transcript
    is present at normal levels and the truncated protein can be expressed from a
    transgene, so this is a loss of adaptor function rather than a loss of the
    transcript.
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      12 homozygous variants remained, but only chr16:28997725 deletion (del) GG
      (RefSeq accession no. NM_001014987.1: c.268_269del) segregated with the
      disease in the family.
    explanation: >-
      Establishes the causal allele by segregation in the first kindred.
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The relative amount of LAT mRNA in patient’s sorted CD4 CD45R0 T cells was
      within the range of three different healthy controls (Fig. 2 C), indicating
      that the mutation does not interfere with transcript stability.
    explanation: >-
      Shows the transcript is stable, which locates the defect in the protein's
      adaptor function.
diagnosis:
- name: Whole exome sequencing
  description: >-
    The diagnosis in every reported case was molecular. Exome sequencing identified
    the causal homozygous variant in the first kindred and in the Iranian SCID
    series, with Sanger confirmation in the parents; the second pedigree was solved
    by homozygosity mapping followed by Sanger sequencing of LAT.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:37516813
    reference_title: "Clinical, immunological and molecular findings of 8 patients with typical
      and atypical severe combined immunodeficiency: identification of 7 novel mutations by whole
      exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, all variants were confirmed in patients and their parents as a
      heterozygous state by Sanger sequencing.
    explanation: >-
      Describes the exome-plus-Sanger route by which the LAT variant in this
      series was identified and confirmed in the family.
  - reference: PMID:27522155
    reference_title: Mutations in linker for activation of T cells (LAT) lead to a novel form
      of severe combined immunodeficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygosity mapping was used to identify potential defective genes.
    explanation: >-
      The alternative route used in the consanguineous SCID pedigree, which
      narrowed the search before Sanger sequencing of LAT.
- name: Flow cytometric assessment of LAT protein expression
  description: >-
    LAT protein was undetectable by flow cytometry with an antibody against the
    intracytoplasmic part of the protein in the index patient's CD4 T cells, while
    the heterozygous sibling showed normal levels in most cells. The assay
    separates affected from carrier, but note it reads the cytoplasmic region, so a
    truncated protein that is still made will read as absent.
  diagnosis_term:
    preferred_term: immunological flow cytometry
    term:
      id: NCIT:C113003
      label: Immunological Flow Cytometry
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The LAT protein, however, could not be detected by flow cytometry using an
      antibody directed against the intracytoplasmic part of LAT in CD4 T cells
      (Fig. 2 D) and by Western blotting of patient-derived EBV lines using a
      polyclonal antibody against LAT (not depicted).
    explanation: >-
      Documents the flow cytometric finding and the antibody's target, which is
      what the caveat in the description rests on.
treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    The only reported treatment that addresses the disease rather than its
    complications. The index patient of the first kindred was transplanted at eight
    years from a fully matched heterozygous sibling; at one year the graft showed
    full donor chimerism with resolution of the opportunistic infections and the
    autoimmune cytopenias and clearance of the skin infiltrates, off
    immunosuppression. This is one transplanted patient with one year of follow-up,
    so it establishes feasibility rather than long-term outcome.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Impaired T Cell Activation and Proliferation
    treatment_effect: RESTORES
    description: >-
      Donor-derived lymphocytes carry intact LAT and can assemble the TCR
      signalosome.
  - target: Loss of LAT-Dependent Restraint on T Cell Responses
    treatment_effect: RESTORES
    description: >-
      Replacing the LAT-deficient T-cell compartment removed the autoimmune
      cytopenias and the skin infiltrates in the transplanted patient.
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 1-yr follow-up demonstrated full donor chimerism, resolution of
      opportunistic infections and autoimmune cytopenias, and disappearance of
      skin infiltrates without any immunosuppressive treatment.
    explanation: >-
      Reports the outcome of the one transplanted patient, covering both the
      infectious and the autoimmune arms.
- name: Immunoglobulin Replacement
  description: >-
    Immunoglobulin replacement was started in the index patient at eight years once
    panhypogammaglobulinaemia had developed, and was given alongside antiviral
    therapy during his CMV and adenovirus episode, with gradual improvement. It
    covers the antibody deficiency and does nothing for the cellular defect.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: immunoglobulin therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Defective T-Dependent Antibody Production
    treatment_effect: BYPASSES
    description: >-
      Passive antibody substitutes for the antibody the patient cannot make; it
      does not restore helper function.
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 8, IgG replacement therapy was started.
    explanation: >-
      Records the use of immunoglobulin replacement in the index patient.
- name: Antiviral Therapy
  description: >-
    Antiviral treatment was used for the CMV and adenovirus episode in the index
    patient, with gradual improvement in respiratory function. The oldest sibling
    nonetheless died of disseminated CMV while awaiting transplant, so antiviral
    therapy contains rather than resolves the viral susceptibility.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antiviral therapy
    term:
      id: NCIT:C16119
      label: Antiviral Therapy
  target_mechanisms:
  - target: Severe cytomegalovirus infection
    treatment_effect: MODULATES
    description: >-
      Suppresses viral replication without restoring the T-cell immunity that
      would normally control it.
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On antiviral and IgG replacement therapy, he improved gradually, and genetic
      diagnosis was performed.
    explanation: >-
      Records the antiviral treatment and the clinical response in the index
      patient.
- name: Systemic Corticosteroid Therapy
  description: >-
    Corticosteroids were used in all three siblings for the autoimmune cytopenias.
    They controlled them incompletely: the oldest sibling's disease was described
    as treatment-resistant and went on to splenectomy, and the index patient
    remained on steroids for severe Evans syndrome from six years until transplant.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: systemic corticosteroid therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  target_mechanisms:
  - target: Polyclonal B Cell Activation and Autoantibody Production
    treatment_effect: MODULATES
    description: >-
      Broad immunosuppression dampens the autoantibody-mediated cytopenias without
      correcting the signalling lesion that drives them.
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      From the age of 6 yr, he was treated with steroids for severe Evans
      syndrome.
    explanation: >-
      Records corticosteroid use for the autoimmune cytopenias in the index
      patient.
- name: Splenectomy
  description: >-
    Splenectomy was performed in the oldest sibling at seven years for progressive
    treatment-resistant autoimmune cytopenia. It did not alter the course: he died
    two years later of disseminated CMV while awaiting transplantation.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: splenectomy
    term:
      id: NCIT:C15328
      label: Splenectomy
  target_mechanisms:
  - target: Autoimmune hemolytic anemia
    treatment_effect: MODULATES
    description: >-
      Removes the principal site of antibody-coated cell destruction; it does not
      reduce autoantibody production.
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For progressive treatment–resistant autoimmune cytopenia, he was
      splenectomized at the age of 7 yr, but at age 9, awaiting hematopoietic stem
      cell transplantation, he died because of disseminated CMV infection with
      pulmonary involvement.
    explanation: >-
      Records the splenectomy, its indication, and the outcome that followed.
animal_models:
- name: Lat-null mouse
  species: Mouse
  genotype: Lat knockout (Lat-/-)
  publication: PMID:10204488
  description: >-
    The original null model. Thymocyte development is blocked within the
    CD4-CD8- double-negative compartment and no mature peripheral T cells appear,
    while B cells are normal. It established that LAT is required for T-cell development,
    and its block is more complete than any human patient's.
  modeled_mechanisms:
  - target: Arrest of Thymic T Cell Development
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reproduces the requirement for LAT in thymic development, and locates the
      checkpoint, but at a severity the human disease does not reach.
    limitations: >-
      Mice lacking LAT, and mice in which all four cytoplasmic tyrosines are
      replaced, have no peripheral T cells at all. Patients homozygous for an
      allele that removes the same four tyrosines still produce mature T cells,
      and in one kindred those T cells were present in normal numbers for years. A
      study reading peripheral T-cell numbers off this model would describe a more
      absolute deficit than patients have.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The murine developmental block is complete at the DN3 stage; the human
        block is partial and variable despite an allele that removes the same four
        phosphorylation sites. No compensating adaptor has been found to explain
        the difference, so the divergence is unexplained rather than attributable
        to a known paralogue.
    evidence:
    - reference: PMID:10204488
      reference_title: Essential role of LAT in T cell development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Flow cytometric analysis revealed normal B cell populations but the
        absence of any mature peripheral T cells. Intrathymic development was
        blocked within the CD4- CD8- stage.
      explanation: >-
        States the model's developmental block and its stage, which is the claim
        this link makes.
    - reference: PMID:27353087
      reference_title: Human LAT mutation results in immune deficiency and autoimmunity but also
        raises questions about signaling pathways.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Germline deletion of LAT in mice results in profound early thymocyte
        developmental arrest, resulting in complete absence of peripheral T cells.
      explanation: >-
        A commentary stating the mouse phenotype in the sentence that contrasts it
        with the patients, which is what the limitation records.
  evidence:
  - reference: PMID:10204488
    reference_title: Essential role of LAT in T cell development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To probe the role of LAT in T cell development, the LAT gene was disrupted
      by targeting.
    explanation: >-
      Establishes how the model was made.
- name: LatY136F knock-in mouse
  species: Mouse
  genotype: Lat Y136F knock-in (homozygous)
  publication: PMID:12065840
  description: >-
    A knock-in replacing the PLC-gamma1 docking tyrosine and leaving the other
    three intact. Unlike the null, these mice pass the developmental block
    partially and then accumulate type 2 helper T cells, developing a polyclonal
    lymphoproliferative disorder, hypergammaglobulinaemia and systemic autoimmunity
    with nephritis. It is the model that made the immunodeficiency-with-autoimmunity
    combination intelligible, and it is a closer counterpart to the human CID
    presentation than the null is.
  modeled_mechanisms:
  - target: Loss of LAT-Dependent Restraint on T Cell Responses
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces the central paradox of the human disease: an allele that impairs
      receptor signalling produces lymphoproliferation and autoimmunity rather than
      immunological silence.
    limitations: >-
      The mouse allele removes one docking tyrosine, whereas the patients' alleles
      truncate the whole tail, so the model is not genotype-matched. The murine
      disease is also dominated by nephritis and by IgE and IgG1
      hypergammaglobulinaemia, while the patients' autoimmunity is principally
      haematological and their immunoglobulins fall over years.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Systemic autoimmune nephritis with severe proteinuria dominates the murine
        disease; no patient developed nephritis, and the reported human
        autoimmunity is haematological.
    evidence:
    - reference: PMID:12065840
      reference_title: A LAT mutation that inhibits T cell development yet induces lymphoproliferation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mice homozygous for a single tyrosine mutation in LAT (linker for
        activation of T cells) exhibited an early block in T cell maturation but
        later developed a polyclonal lymphoproliferative disorder and signs of
        autoimmune disease.
      explanation: >-
        States the model's combination of developmental block and later
        lymphoproliferative autoimmunity, which is the mechanism this link
        attributes to it.
    - reference: PMID:18209052
      reference_title: Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently
        of TCR-MHC engagement and is insensitive to the action of Foxp3+ regulatory T cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This abnormal status confers Lat(Y136F) CD4 T cells with the ability to
        trigger the production of Abs and of autoantibodies in a TCR-independent,
        quasi-mitogenic fashion.
      explanation: >-
        Characterises the mechanism as receptor-independent rather than
        autoreactive, which is what the node claims about loss of restraint.
  - target: Th2 Effector Skewing
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The type 2 skew is reproduced in full, and was described in the model before
      it was observed in patients.
    limitations: >-
      The model's type 2 response drives tissue eosinophilia and massive IgE and
      IgG1 plasma cell maturation; in patients it was demonstrated as constitutive
      IL-4 production by CD4 and gamma-delta T cells, with raised IgE recorded in
      only one of the three siblings.
    evidence:
    - reference: PMID:12065839
      reference_title: Induction of T helper type 2 immunity by a point mutation in the LAT adaptor.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This exaggerated TH2 differentiation caused tissue eosinophilia and
        massive maturation of plasma cells secreting to immunoglobulins of the E
        and G1 isotypes.
      explanation: >-
        Describes the type 2 phenotype of the model that this link cites it for.
  - target: Polyclonal B Cell Activation and Autoantibody Production
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Supplies the step from aberrant helper T cells to polyclonal, non-antigen
      driven B-cell activation and systemic autoimmunity.
    limitations: >-
      The autoimmune target organ differs: the model develops nephritis with IgE
      autoantibody deposits and severe proteinuria, whereas the patients'
      autoantibody disease was directed at blood cells and, in one, at ADAMTS13.
    evidence:
    - reference: PMID:16887989
      reference_title: The Th2 lymphoproliferation developing in LatY136F mutant mice triggers
        polyclonal B cell activation and systemic autoimmunity.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These results show that Th2 cells developing in Lat(Y136F) mice can
        trigger polyclonal B cell activation and thereby lead to systemic
        autoimmune disease.
      explanation: >-
        States the causal step from the helper T-cell abnormality to polyclonal
        B-cell activation and autoimmunity.
  evidence:
  - reference: PMID:12065840
    reference_title: A LAT mutation that inhibits T cell development yet induces lymphoproliferation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results identify a critical role for integrated PLC-gamma1 and Ras-Erk
      signaling through LAT in T cell development and homeostasis.
    explanation: >-
      The model's own conclusion about what the mutated docking site does, which
      establishes what the model is a model of.
discussions:
- discussion_id: mouse_null_overstates_the_human_developmental_block
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Can the LAT-null mouse be used to predict the T-cell compartment of a person
    with LAT deficiency, when the same loss of all four cytoplasmic tyrosines
    abolishes peripheral T cells in the mouse but not in patients?
  attaches_to:
  - pathophysiology#Arrest of Thymic T Cell Development
  - animal_models#Lat-null mouse
  rationale: >-
    This is the mismatch the first human report was built around, and it is not a
    difference of degree at the margins. Mice lacking LAT, and mice in which all
    four tyrosines are replaced by phenylalanine, arrest at the DN3 stage and have
    no peripheral T cells. The patients in the first kindred carry an allele that
    removes those same four tyrosines and still had mature T cells in normal
    numbers at presentation, with the numbers falling only over subsequent years.

    Two candidate explanations were tested and neither survived. A compensating
    adaptor was sought: SIT, TRIM, LAX, LIME and PAG were not differentially
    expressed in the patients' T cells, NTAL/LAB protein was undetectable, and CD6
    transduced into LAT-deficient Jurkat cells did not restore calcium
    mobilisation. Reversion of the mutation and alternative splicing were both
    excluded, by sequencing of sorted T cells and by RNA sequencing. So the
    residual development is unexplained rather than explained by a known
    substitute.

    The practical consequence is narrow enough to use. The null mouse is
    informative about where in thymic development LAT acts and about what the
    adaptor does biochemically; it is not informative about how many T cells a
    patient will have, nor about anything that depends on having a peripheral
    T-cell compartment, which includes the whole autoimmune arm of the human
    disease. For that arm the tyrosine knock-in strains are the better read.
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LAT knockout mice (Zhang et al., 1999b) and mice with targeted replacement
      of all four tyrosine residues (Sommers et al., 2001) lack peripheral T cells
      because of a block at the double-negative 3 stage, whereas in humans, T
      cells lacking all four equivalent tyrosine residues were still present,
      although with a severely disturbed differentiation.
    explanation: >-
      States both halves of the mismatch in one sentence, naming the mouse alleles
      that produce the complete block.
  - reference: PMID:27353087
    reference_title: Human LAT mutation results in immune deficiency and autoimmunity but also
      raises questions about signaling pathways.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      It is possible that some LAT-related molecule might compensate for the loss
      of LAT function in the human, but efforts to identify such molecules were
      not productive.
    explanation: >-
      Records that the obvious explanation was looked for and not found, which is
      why the mismatch is left open.
- discussion_id: residual_calcium_and_nfkb_signalling_is_unexplained
  kind: KNOWLEDGE_GAP
  prompt: >-
    How do patient T cells lacking all four LAT phosphotyrosines still mobilise
    calcium and activate NF-kappaB after receptor cross-linking, when the same
    allele abolishes both in a reconstituted LAT-deficient T-cell line?
  attaches_to:
  - pathophysiology#Failure of TCR Signalosome Assembly
  - pathophysiology#Abolished TCR-Induced ERK Activation
  rationale: >-
    Calcium mobilisation downstream of the receptor is supposed to require
    PLC-gamma1 recruited to the LAT phosphotyrosine at position 132. In the
    patients' own memory CD4 and CD8 T cells, and in their gamma-delta T cells,
    calcium flux after CD3 cross-linking was within the range of healthy controls
    across independent experiments, and IkappaB-alpha degradation proceeded
    normally, while ERK phosphorylation was absent. The same patient allele
    expressed in LAT-deficient Jurkat cells abolished calcium flux, so this is a
    difference between primary human T cells and the cell line rather than between
    the mutant and the wild-type protein.

    A partial account exists for why ERK and calcium come apart: the three distal
    tyrosines recruit Grb2-SOS1 and are required for Ras activation, so a route to
    PLC-gamma1 that bypasses LAT would give inositol trisphosphate and calcium
    without giving ERK. What is missing is the route itself. Resolving it matters
    beyond this disease, because the textbook non-redundancy of LAT in calcium
    signalling is what the patients contradict.
  evidence:
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, to our surprise, Ca2+ mobilization after CD3 cross-linking was
      normal in primary T cells of the index patient, and the sustained T cell
      differentiation in LAT-deficient patients supports the notion of a preserved
      residual TCR signal in vivo.
    explanation: >-
      States the unexpected preserved calcium response in the patient's primary T
      cells, which is the gap.
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, it is unlikely that CD6 replaces LAT function in LAT-deficient
      primary T cells, and the explanation of the preserved Ca2+ flux, NF-κB
      activation in the patient’s T cells, and the persistent T cell
      differentiation remains elusive at this time.
    explanation: >-
      The authors' own statement that the finding is unexplained after the
      candidate substitutes were tested.
- discussion_id: scid_versus_cid_presentation_is_not_yet_explained
  kind: OPEN_QUESTION
  prompt: >-
    Why does the same class of truncating LAT allele produce absent T cells and
    typical SCID in one pedigree and present-but-declining T cells with severe
    autoimmunity in another?
  attaches_to:
  - pathophysiology#Arrest of Thymic T Cell Development
  - pathophysiology#Loss of LAT-Dependent Restraint on T Cell Responses
  rationale: >-
    IUIS records both presentations in a single row, and this entry follows that by
    curating them together. But the two kindreds are genuinely different at the
    bedside: one presented as T-negative SCID with normal B and NK cells, the other
    with normal T-cell numbers, lymphoproliferation and life-threatening autoimmune
    cytopenias from five months of age. Both alleles are truncating.

    Three explanations are available and none can be chosen with three kindreds.
    The alleles truncate at different positions, so a residual product retaining
    some proximal function is possible in one and not the other. The CID kindred's
    own course shows that T-cell numbers fall with time, so the difference may be
    partly one of when the patients were ascertained. And modifier or environmental
    contributions cannot be excluded in pedigrees of this size.
    Recording the question rather than a `has_subtypes` split keeps the entry from
    asserting a stratification the evidence does not yet support.
  evidence:
  - reference: PMID:41608114
    reference_title: "Human inborn errors of immunity: 2024 update on the classification from
      the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      LAT deficiency | LAT | AR | 617514 | Normal to low | Normal to low | High
      | Typical SCID or CID, the latter with adenopathy, splenomegaly,
      recurrent infections, autoimmunity
    explanation: >-
      The classification committee's own record that both presentations belong to
      one condition, which is what makes this an open question rather than a
      lumping error.
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identification of additional patients with possibly different LAT
      mutations will shed further light on the full immunological and clinical
      presentation of human LAT deficiency.
    explanation: >-
      The authors' statement that the phenotypic range is not yet established,
      which is the state this question records.
- discussion_id: il6_dependence_of_the_lymphoproliferative_arm_is_untested_in_patients
  kind: EMERGING_HYPOTHESIS
  prompt: >-
    Is the lymphoproliferative arm of human LAT deficiency IL-6 dependent, as it is
    in the LatY136F mouse, and would IL-6 blockade therefore be a rational bridge
    to transplant?
  attaches_to:
  - pathophysiology#Loss of LAT-Dependent Restraint on T Cell Responses
  - pathophysiology#Polyclonal Lymphoproliferation
  rationale: >-
    In the LatY136F mouse the mutant T cells overproduce IL-6, and crossing the
    strain onto an IL-6-deficient background showed that IL-6 is required for the
    uncontrolled early T-cell expansion; the reduction came from impaired cell
    survival rather than from a further developmental block or more regulatory T
    cells. Aged IL-6-deficient LatY136F mice eventually hyperproliferated and
    developed splenomegaly, but with diminished isotype switching and autoantibody
    production, so IL-6 loss delays and attenuates the syndrome rather than
    abolishing it.

    Nothing equivalent has been measured in patients: no IL-6 level, no IL-6
    pathway readout, and no anti-IL-6 exposure is reported in any of the three
    kindreds. The hypothesis is recorded because the autoimmune arm is what kills
    these children before transplant and there is an approved drug class against
    this target, not because human evidence supports it. Any use would be
    off-label, unstudied in this disease, and taken on a mouse result obtained with
    a different allele.
  evidence:
  - reference: PMID:26034173
    reference_title: The Importance of IL-6 in the Development of LAT-Mediated Autoimmunity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      By crossing LATY136F mice with IL-6-deficient mice, we demonstrated that
      IL-6 is required for uncontrolled T cell expansion during the early stage of
      disease development.
    explanation: >-
      The genetic experiment behind the hypothesis. INDIRECT because it is a mouse
      result on a different allele from the human disease-causing ones, and the
      inference to patients is untested.
  - reference: PMID:26034173
    reference_title: The Importance of IL-6 in the Development of LAT-Mediated Autoimmunity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      In aged IL-6(-/-) LATY136F mice, CD4(+) T cells began to hyperproliferate
      and induced splenomegaly; however, isotype switching and autoantibody
      production were diminished.
    explanation: >-
      Records that removing IL-6 attenuates rather than abolishes the syndrome,
      which is the limit on how much the hypothesis could deliver.
- discussion_id: non_t_lineage_contribution_is_uncharacterised
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does loss of LAT contribute to disease through mast cells, megakaryocytes or
    platelets, in which the adaptor is also expressed but in which no patient has
    been studied?
  attaches_to:
  - pathophysiology#Reduced Cytotoxic Degranulation
  - phenotypes#Decreased natural killer cell degranulation
  rationale: >-
    LAT is expressed in mast cells, natural killer cells, megakaryocytes, platelets
    and early B cells as well as in T cells. The only non-T lineage in which
    LAT-deficient patients have been assessed is the NK compartment, where
    degranulation and cytotoxicity were reduced but not absent. No report gives
    platelet function, bleeding history, mast-cell function or allergic history in a
    LAT-deficient patient, so whether the expression pattern translates into
    clinical features outside the T-cell compartment is unknown.

    This is worth recording rather than leaving implicit because the inference is
    tempting and unsupported: an adaptor expressed in platelets is not thereby a
    platelet disease, and the thrombocytopenia the patients did have was
    autoantibody-mediated, which is a T-cell-driven route to the same laboratory
    finding. Distinguishing the two would need platelet function testing in a
    patient, which nobody has published.
  evidence:
  - reference: PMID:16102570
    reference_title: Role of the LAT adaptor in T-cell development and Th2 differentiation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Although LAT is also expressed in mast cells, natural killer cells,
      megakaryocytes, platelets, and early B cells, the present review
      specifically illustrates the role LAT plays in the development and function
      of mouse T cells.
    explanation: >-
      Establishes the expression pattern outside T cells that makes the question
      worth asking.
  - reference: PMID:27242165
    reference_title: Early onset combined immunodeficiency and autoimmunity in patients with
      loss-of-function mutation in LAT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, the degranulation of LATmut CTLs after stimulation with
      anti-CD3/anti-CD28 beads (Fig. 6 D) and of patient-derived NK cells after
      stimulation with the K562 cell line was reduced (Fig. 6 E), although not
      absent.
    explanation: >-
      The one non-T lineage measurement that exists in patients, which is where
      the available human evidence stops.

📚

References & Deep Research

References

PMID:27242165

Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT.

No top-level findings curated for this source.

PMID:27522155

Mutations in linker for activation of T cells (LAT) lead to a novel form of severe combined immunodeficiency.

No top-level findings curated for this source.

PMID:37516813

Clinical, immunological and molecular findings of 8 patients with typical and atypical severe combined immunodeficiency: identification of 7 novel mutations by whole exome sequencing.

No top-level findings curated for this source.

PMID:27353087

Human LAT mutation results in immune deficiency and autoimmunity but also raises questions about signaling pathways.

No top-level findings curated for this source.

PMID:41608114

Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee.

No top-level findings curated for this source.

PMID:9489702

LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation.

No top-level findings curated for this source.

PMID:26354432

The linker for activation of T cells (LAT) signaling hub: from signaling complexes to microclusters.

No top-level findings curated for this source.

PMID:17534068

Th2 lymphoproliferative disorders resulting from defective LAT signalosomes.

No top-level findings curated for this source.

PMID:16102570

Role of the LAT adaptor in T-cell development and Th2 differentiation.

No top-level findings curated for this source.

PMID:10204488

Essential role of LAT in T cell development.

No top-level findings curated for this source.

PMID:12065840

A LAT mutation that inhibits T cell development yet induces lymphoproliferation.

No top-level findings curated for this source.

PMID:12065839

Induction of T helper type 2 immunity by a point mutation in the LAT adaptor.

No top-level findings curated for this source.

PMID:16887989

The Th2 lymphoproliferation developing in LatY136F mutant mice triggers polyclonal B cell activation and systemic autoimmunity.

No top-level findings curated for this source.

PMID:18209052

Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently of TCR-MHC engagement and is insensitive to the action of Foxp3+ regulatory T cells.

No top-level findings curated for this source.

PMID:19682930

Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor.

No top-level findings curated for this source.

PMID:20542732

LAT signaling pathology: an "autoimmune" condition without T cell self-reactivity.

No top-level findings curated for this source.

PMID:26034173

The Importance of IL-6 in the Development of LAT-Mediated Autoimmunity.

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Ultra-rare. Every claim about patients in this entry rests on three published kindreds: three siblings of an Israeli Arab consanguineous family homozygous for LAT c.268_269delGG (Keller et al., J Exp Med 2016), a pedigree with a homozygous frameshift abolishing LAT expression (Bacchelli et al., JACI 2017, which reports affected family members without giving a count in its abstract), and one patient homozygous for LAT p.Y207fsTer33 in an eight-patient SCID exome series (Alizadeh et al., Genes Immun 2023). `frequency` is deliberately left unset on every phenotype: with a denominator this small any enum value would assert a population rate that no source supports, and the evidence `explanation` says instead how many patients showed a finding. The two presentations were curated as one entry rather than split. IUIS 2024 carries typical SCID and the CID-with-autoimmunity picture in a single row, and the truncating variants behind them remove the same cytoplasmic tyrosines, so there is no second pathomechanism to separate. Whether the difference is allelic, modifier-driven or an artefact of when the patients were ascertained cannot be answered from three kindreds; it is recorded as an open question in `discussions` rather than as a `has_subtypes` split. No GeneReviews chapter exists for LAT deficiency: `just check-genereviews` reports NO_CHAPTER against the committed Bookshelf index with the synonyms above in place. The phenotype baseline here is therefore the primary literature, and the great majority of it is the Keller kindred, the only report with full-text clinical and immunological detail. The umbrella entry `Severe_Combined_Immunodeficiency` carries LAT as one of its causal gene rows. That entry is untouched here; this one is the gene-specific pathomechanism it points at. Sibling entries in the same signalling chain are already curated: ZAP70 deficiency (`ZAP70_Deficiency`, the kinase that phosphorylates LAT) and CD3gamma deficiency (`Combined_Immunodeficiency_Due_To_CD3gamma_Deficiency`, upstream at the receptor). Keller et al. note the clinical resemblance to ZAP70, ITK and LCK deficiency and what separates each: the prominent CD8 reduction in ZAP70 deficiency, the absent calcium signal in ITK deficiency, and the preserved ERK signal in LCK deficiency. The ERK-abolished, calcium-preserved pattern is what distinguishes LAT deficiency from those. LAT is expressed in mast cells, natural killer cells, megakaryocytes, platelets and early B cells as well as T cells, and no patient has been studied for platelet or mast-cell function. The one non-T lineage with human data is the NK compartment, whose degranulation was reduced but not absent. The gap is recorded in `discussions` rather than filled by inference from expression data. No `conforms_to` module was declared. `kb/modules/` was searched (`ls kb/modules/`, plus `rg -il "T cell receptor|TCR signal" kb/modules`) for a TCR signalling or lymphocyte activation module and none exists. If one is ever written, this entry, ZAP70 deficiency and CD3gamma deficiency are its first conformers. Three things the deep-research report proposed are deliberately not curated here, because no source ties them to this disease rather than to severe combined immunodeficiency in general: detection by TREC newborn screening, the standard SCID supportive-care package (Pneumocystis prophylaxis, irradiated and CMV-safe blood products, avoidance of live vaccines), and survival figures taken from general SCID transplant cohorts. Eosinophilia is omitted for a different reason: it is a feature of the LatY136F mouse, and no eosinophil count is reported for any patient.

Create: LAT_Deficiency · 2026-09-29T21:31:36Z · View source

Created the LAT deficiency entry (MONDO:0044721, IMD52, LAT hgnc:18874, autosomal recessive) from the primary literature plus a committed OpenScientist deep-research report. Deep research: research/LAT_Deficiency-deep-research-openscientist.md, with its citations sidecar and the two provider artifacts (final_report.html/pdf). Its own frontmatter reports 13/13 references resolved, 0 unresolved, 11/13 on topic, and term validation with 35/38 terms resolved but 10 mislabelled and needs_review true. 'just preflight-dr research/LAT_Deficiency-deep-research-openscientist.md MONDO:0044721' returns PASS with LAT mentioned 71 times and the MONDO OMIM (617514) matching. None of the report's suggested CURIEs was copied: every ontology identifier in the entry was looked up through ols: or the committed term caches at the point of writing. Two of the report's bindings were wrong in ways that would have propagated - HP:0004810 offered for autoimmune haemolytic anaemia is Congenital hypoplastic anaemia, and HP:0002720 offered for hypogammaglobulinaemia is Decreased circulating IgA concentration - and the report also gives HGNC:6533 for LAT, where the gene is hgnc:18874. Sources. Three human reports exist: Keller 2016 (PMID:27242165, full text, three siblings, the only report with detailed clinical and immunological data), Bacchelli 2017 (PMID:27522155, abstract only, the SCID pedigree) and Alizadeh 2023 (PMID:37516813, one patient in a SCID exome series). Mechanism and model content comes from PMID:9489702, PMID:26354432, PMID:17534068, PMID:16102570, PMID:10204488, PMID:12065840, PMID:12065839, PMID:16887989, PMID:18209052, PMID:19682930, PMID:20542732 and PMID:26034173; the IUIS 2024 classification row is PMID:41608114, already in the committed cache. Content. Sixteen pathophysiology nodes run as a single chain from the biallelic truncating allele through loss of the cytoplasmic phosphotyrosines, failure of signalosome assembly, and abolished ERK activation, then branch into the developmental arrest, the loss of LAT-dependent restraint that produces lymphoproliferation and autoimmunity, and the progressive immune collapse. Twenty-eight phenotypes, all causally connected (just list-disconnected-phenotypes reports 28/28). Both mouse models carry modeled_mechanisms with limitations and typed SPECIES_MISMATCH divergences. Five discussions record the mouse/human developmental mismatch, the unexplained residual calcium and NF-kappaB signalling, the SCID versus CID presentation question, the untested IL-6 hypothesis, and the uncharacterised non-T lineages. Judgement calls. The SCID and CID presentations are curated as one entry, following the single IUIS row, with the difference recorded as an OPEN_QUESTION rather than a has_subtypes split. frequency is unset throughout because the denominator is three kindreds. A recurrent-gastroenteritis phenotype was dropped: HPO has no term for a single episode and the source does not say it recurred. TREC newborn screening, the general SCID supportive-care package and general SCID survival figures were surfaced by the report and left out because no source ties them to this disease; the reasons are recorded in notes. Validation: just validate, just validate-terms, just check-entity-refs, just check-causal-targets, just check-duplicate-keys, just check-qualifier-terms, just check-enum-values, just check-coarse-phenotypes, just check-snippet-length, just check-title-snippets, just check-snippet-grading, just check-folded-hyphens, just check-environmental-evidence and just check-term-cache-integrity all pass. just count-verified-snippets reports 96/96 verified. just validate-disorders passes with 96 snippets and 113 titles checked and no issues. just check-genereviews reports NO_CHAPTER offline and with --online, so the note that no GeneReviews chapter exists is verified.

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LAT Deficiency (Immunodeficiency-52): A Comprehensive Disease Characterization

openscientist-autonomous 13 citations 2026-09-29T20:59:52.615580

LAT Deficiency (Immunodeficiency-52): A Comprehensive Disease Characterization

Disease: LAT Deficiency · MONDO: MONDO:0044721 · OMIM: #617514 (Immunodeficiency-52) · ORPHA: 504523 · Gene: LAT (HGNC:6533) · Category: Mendelian, autosomal recessive inborn error of immunity

Summary

LAT deficiency is an ultra-rare (<1/1,000,000) autosomal-recessive inborn error of immunity caused by biallelic loss-of-function (truncating) mutations in LAT (Linker for Activation of T cells; chromosome 16p11.2), the transmembrane adaptor protein that nucleates the T-cell receptor (TCR) signalosome. Loss of LAT abolishes ERK/Ras-MAPK signaling and cripples PLCγ1-dependent Ca²⁺/NFAT signaling downstream of ZAP-70, producing a paradoxical clinical picture: a combined immunodeficiency (T–B+NK+ SCID with recurrent and opportunistic infections) coexisting with severe Th2-skewed immune dysregulation (autoimmune cytopenias, lymphoproliferation, hypergammaglobulinemia, elevated IgE).

The disease was first described in humans in 2016 (Keller et al., three siblings of a consanguineous family) and has since been confirmed in at least two additional independent consanguineous kindreds (Bacchelli 2017; Alizadeh 2023), giving a worldwide total of fewer than ~20 reported patients. In every case the variants are germline, biallelic, and truncating (nonsense or frameshift), removing the cytoplasmic tail of LAT with its critical signaling tyrosines; parents are asymptomatic heterozygous carriers. Symptom onset is in the first months of life (5–10 months in the index kindred), and the disease is usually fatal in early childhood without allogeneic hematopoietic stem cell transplantation (HSCT), which is the only curative treatment.

The human disease sits mechanistically between two long-studied mouse models: the complete Lat-null knockout (which arrests thymocyte development, modeling the immunodeficiency arm) and the LatY136F knock-in (which disrupts only the PLCγ1 docking site and produces a Th2 lymphoproliferative/autoimmune syndrome, modeling the autoimmunity arm). This dual phenotype reflects LAT's dual biological role as both a positive activator and a negative homeostatic regulator of TCR signaling. Because LAT deficiency causes T-cell lymphopenia, it is detectable by population-based TREC (T-cell receptor excision circle) newborn screening for SCID, enabling early diagnosis and pre-symptomatic transplantation, which markedly improves survival.

Section 1 — Disease Information

Overview. LAT deficiency is a Mendelian primary immunodeficiency (inborn error of immunity) in which the T-cell receptor signaling adaptor LAT is absent or non-functional. It manifests as a combined immunodeficiency accompanied by severe, often early and dominant, autoimmune/immune-dysregulatory disease. Depending on the residual T-cell output, patients are classified along a spectrum from "combined immunodeficiency with autoimmunity" to frank T–B+NK+ severe combined immunodeficiency (SCID).

Key identifiers.

Resource	Identifier
OMIM (phenotype)	#617514 — IMMUNODEFICIENCY 52 (IMD52)
OMIM (gene)	602354 (LAT*)
Orphanet	ORPHA:504523 — "T-B+NK+ severe combined immunodeficiency due to LAT deficiency"
MONDO	MONDO:0044721
ICD-10	D81.2 (other combined immunodeficiencies)
ICD-11	4A01.10
UMLS / GTR	C4479588
GARD	17938
Gene	LAT, HGNC:6533, NCBI Gene 27040, UniProt O43561, chromosome 16p11.2

Synonyms / alternative names. Immunodeficiency 52 (IMD52); combined immunodeficiency due to LAT deficiency; T-B+NK+ SCID due to LAT deficiency; LAT signalosome deficiency. (LAT = "Linker for Activation of T cells.")

Data source. All information derives from aggregated disease-level resources (OMIM, Orphanet) and individual patient case reports/kindreds in the primary literature — there is no EHR/registry-level dataset for this ultra-rare condition. Evidence is a mixture of human clinical case reports and mechanistic model-organism (mouse) and in vitro studies.

Section 2 — Etiology

Primary cause (genetic). Biallelic (homozygous or compound heterozygous) loss-of-function mutations in LAT. All reported families to date were consanguineous, so the operative genetic mechanism is homozygosity-by-descent of a truncating allele (PMID: 27242165; PMID: 27522155; PMID: 37516813).

Genetic risk factors. The only established risk factor is inheriting two defective LAT alleles. Consanguinity is the dominant epidemiological risk factor (raises the probability of homozygosity for a rare recessive allele). Heterozygous carriers (including all reported parents) are asymptomatic.

Environmental / protective factors. As a monogenic Mendelian disorder, there are no established environmental risk factors, protective factors, or gene–environment interactions that initiate the disease. Environmental exposures (pathogens) act only as triggers that unmask the immunodeficiency (e.g., CMV, VZV, toxoplasma infections), not as causes. No protective modifier alleles have been reported. This section is largely not applicable beyond the genetic cause.

Section 3 — Phenotypes

Phenotype data derive principally from the first kindred (Keller et al. 2016, three siblings, PMID: 27242165) supplemented by the SCID-presenting kindreds (PMID: 27522155; PMID: 37516813).

"The three patients presented from early childhood with combined immunodeficiency and severe autoimmune disease" — Keller et al. (PMID: 27242165)

Phenotype	Type	HPO term	Onset / severity / frequency
Combined immunodeficiency / recurrent infections	Clinical sign	HP:0005387 (combined immunodeficiency)	Infantile (5–10 mo); severe; core feature in all
Autoimmune hemolytic anemia	Lab/clinical	HP:0004810	Childhood; severe (fatal in one patient)
Immune thrombocytopenia	Lab/clinical	HP:0001973	Childhood; severe
Generalized lymphadenopathy	Physical sign	HP:0002716	Childhood; variable
Splenomegaly / hepatosplenomegaly	Physical sign	HP:0001744 / HP:0001433	Childhood; massive in index patient
Bronchiectasis / chronic lung disease	Physical sign	HP:0002110	Childhood; from recurrent respiratory infection
Opportunistic infection (CMV, VZV, toxoplasma)	Clinical sign	—	Infancy–childhood; life-threatening
Recurrent gastroenteritis / enteropathy	Symptom	HP:0004385-like	Childhood
Skin nodules / edematous purple-red lesions	Physical manifestation	HP:0011355	Childhood; variable
T lymphocytopenia / reduced T cells	Lab abnormality	HP:0005403	Congenital/progressive; universal
Eosinophilia	Lab abnormality	HP:0001880	Childhood; from Th2 skewing
Elevated serum IgE (and high IgG1)	Lab abnormality	HP:0003212	Childhood; from Th2 skewing
Hypogammaglobulinemia (may develop)	Lab abnormality	HP:0002720	Variable/progressive

Onset: neonatal-to-infantile (first months of life). Severity: severe. Progression: progressive combined immune deficiency with superimposed episodic autoimmune crises. Quality of life / outcome: profound — of the three index siblings, two died in childhood (one at age 9 from disseminated CMV following splenectomy; one at age 2 from AIHA plus thrombocytopenia) and one survived after HSCT at age 8.

"manifesting by a progressive combined immune deficiency with severe autoimmune disease" — Keller et al. (PMID: 27242165)

Section 4 — Genetic / Molecular Information

Causal gene. LAT — Linker for Activation of T cells. HGNC:6533; NCBI Gene 27040; OMIM gene 602354; UniProt O43561; chromosome 16p11.2*. LAT is a palmitoylated transmembrane adaptor localized to membrane rafts with a short extracellular domain and a long cytoplasmic tail bearing multiple tyrosines.

Pathogenic variants (all germline, biallelic, loss-of-function):

Kindred	Variant	Type	Consequence
Keller 2016 (PMID: 27242165)	Homozygous nonsense in exon 5	Nonsense	Premature stop codon deleting most of the cytoplasmic tail, including the critical signaling tyrosines
Bacchelli 2017 (PMID: 27522155)	Novel homozygous frameshift	Frameshift	Premature stop, truncation → complete loss of function and loss of expression
Alizadeh 2023 (PMID: 37516813)	Homozygous p.Y207fsTer33	Frameshift	Truncated protein; SCID/leaky-SCID

"we describe the first kindred with defective LAT signaling caused by a homozygous mutation in exon 5, leading to a premature stop codon deleting most of the cytoplasmic tail of LAT, including the critical tyrosine residues for signal propagation" — PMID: 27242165

"a premature stop codon and protein truncation leading to complete loss of function and loss of expression of LAT" — PMID: 27522155

Variant classification (ACMG/AMP): truncating variants in a gene with an established loss-of-function disease mechanism, segregating with disease in consanguineous families → pathogenic. Allele frequency: the specific variants are private/ultra-rare (essentially absent from gnomAD). Somatic vs germline: germline. Functional consequence: loss of function (null); no gain-of-function or dominant-negative human alleles reported (note: the mouse LatY136F is a separation-of-function research allele, not a human disease variant).

Modifier genes / epigenetics / chromosomal abnormalities: none established for the human disease. No large-scale cytogenetic changes; this is a single-gene point/frameshift disorder.

Section 5 — Environmental Information

Not applicable as a cause. There are no environmental factors, lifestyle factors, or infectious agents that cause LAT deficiency. Infectious agents (CMV, varicella-zoster virus, Toxoplasma gondii, common bacterial respiratory pathogens) are downstream consequences of the immunodeficiency and drive much of the morbidity and mortality, but they do not initiate the disease.

Section 6 — Mechanism / Pathophysiology

Ordered causal chain

A biallelic truncating LAT variant results in loss of LAT protein (or a tail-truncated protein lacking its cytoplasmic tyrosines) (PMID: 27242165, PMID: 27522155).
Upon TCR engagement, Lck→ZAP-70 phosphorylation of LAT cannot occur, which leads to failure to assemble the LAT signalosome (PLCγ1, Grb2/SOS, GADS, SLP-76) at the plasma membrane (PMID: 18231606).
Absent signalosome abolishes Ras–ERK/MAPK signaling completely and impairs PLCγ1-dependent Ca²⁺/NFAT signaling, while NF-κB signaling is partially preserved (PMID: 27242165).
Defective proximal TCR signal transduction impairs thymic positive selection and peripheral T-cell activation, resulting in T-cell lymphopenia / absent T cells with absent proliferative responses (PMID: 27522155). This branches:
Branch A (immunodeficiency): reduced/absent functional T cells lead to combined immunodeficiency → recurrent bacterial, viral, and opportunistic infections (CMV, VZV, toxoplasma).
Branch B (autoimmunity/dysregulation, inferred largely from mouse): loss of LAT's negative-regulatory / homeostatic function permits TCR–MHC-independent, "quasi-mitogenic" expansion of Th2-skewed CD4⁺ T cells (PMID: 18209052; PMID: 16887989), a process that is IL-6-dependent in its early phase (PMID: 26034173).
Th2 hyperactivity drives polyclonal B-cell activation → IgG1/IgE hypergammaglobulinemia, eosinophilia, and autoantibodies leading to hematologic autoimmunity (AIHA, ITP), lymphoproliferation (lymphadenopathy, splenomegaly), and tissue immunopathology (immune-complex nephritis in mice).

"residual T cells were able to induce Ca(2+) influx and nuclear factor (NF) κB signaling, whereas extracellular signal-regulated kinase (ERK) signaling was completely abolished" — PMID: 27242165

"LAT phosphorylation results in the recruitment of a signalosome including PLCgamma1, Grb2/SOS, GADS and SLP-76" — PMID: 18231606

Signalosome schematic

      TCR engagement
   │
Lck → ZAP-70
   │  (phosphorylates LAT tyrosines)
   ▼
   ┌─────────────────── LAT (membrane raft) ───────────────────┐
   │        │              │              │            │        │
 PLCγ1   Grb2/SOS        GADS          SLP-76        Itk/Vav1   │
   │        │                             │                     │
  Ca²⁺/    Ras→ERK/MAPK              (integrin activation:      │
  NFAT     (ABOLISHED)                Rap1/talin/actin)         │
 (impaired)                                                     │
   └──────── LOSS OF LAT → no signalosome → branches A & B ─────┘

Molecular pathways: TCR proximal signaling; Ras–MAPK/ERK (KEGG/Reactome "TCR signaling"); PLCγ1–Ca²⁺–NFAT; PI3K and NF-κB (partially preserved). Cellular processes: thymocyte development/positive selection, T-cell activation/proliferation, immune homeostasis (dysregulated), inflammation. Protein dysfunction: loss of function of the adaptor (no scaffold for signalosome assembly). Immune involvement: simultaneous immunodeficiency and autoimmunity/immune dysregulation. Metabolic/biochemical: the defect is a signaling/adaptor defect, not an enzymopathy.

LAT is expressed beyond T cells — in mast cells, NK cells, megakaryocytes, platelets, and early B cells — so non-T lineages may contribute, though human phenotypes there are not well documented.

"Although LAT is also expressed in mast cells, natural killer cells, megakaryocytes, platelets, and early B cells" — PMID: 16102570

"This unexpected finding revealed that LAT also constitutes a negative regulator of TCR signalling and T cell homeostasis" — PMID: 17534068

Suggested GO terms: GO:0050852 (T cell receptor signaling pathway), GO:0070374 (positive regulation of ERK cascade), GO:0002250 (adaptive immune response), GO:0045058 (T cell selection). Cellular component: GO:0005886 (plasma membrane), GO:0045121 (membrane raft). CL terms: CL:0000084 (T cell), CL:0000624 (CD4+ T cell), CL:0000097 (mast cell), CL:0000623 (NK cell).

Section 7 — Anatomical Structures Affected

Primary — immune/hematopoietic system (UBERON:0002405): - Thymus (UBERON:0002370) — impaired T-cell development - Bone marrow (UBERON:0002371) — hematopoietic source; HSCT target - Spleen (UBERON:0002106) — splenomegaly - Lymph nodes (UBERON:0000029) — lymphadenopathy - Peripheral blood (UBERON:0000178) — lymphopenia, cytopenias

Secondary organ involvement: - Lung (UBERON:0002048) — bronchiectasis, recurrent pneumonia - Liver (UBERON:0002107) — hepatomegaly - Skin (UBERON:0002097) — inflammatory nodules - Gastrointestinal tract (UBERON:0000160) — gastroenteritis/enteropathy - Kidney (UBERON:0002113) — immune-complex nephritis (documented in mouse model)

Cell level: T lymphocytes (CL:0000084), especially CD4⁺ Th2 cells (CL:0000624); reactive B cells; mast cells/NK cells/platelets express LAT. Subcellular: plasma membrane (GO:0005886), membrane raft (GO:0045121). Lateralization: systemic/bilateral (not applicable as a focal lateralized disease).

Section 8 — Temporal Development

Onset: congenital defect with clinical onset in the first months of life (5–10 months in the index kindred); insidious-to-subacute in the immunodeficiency arm, with episodic autoimmune crises. Progression: progressive combined immune deficiency; the autoimmune cytopenias are episodic/relapsing and can be acutely life-threatening. Course/duration: chronic and lifelong; without HSCT the natural history is high childhood mortality. Remission: treatment-induced remission via HSCT (curative); spontaneous remission does not occur. Critical period: the neonatal-to-infancy window — early (pre-symptomatic) diagnosis via newborn screening and prompt HSCT is the key opportunity for intervention.

Section 9 — Inheritance and Population

Epidemiology. Ultra-rare: Orphanet lists prevalence <1/1,000,000. Fewer than ~20 patients have been reported worldwide (Keller 2016, Bacchelli 2017, Alizadeh 2023 kindreds). No reliable incidence figure exists; as a T-cell-lymphopenic SCID it falls within the aggregate SCID birth prevalence detected by newborn screening (e.g., ~1:46,753 in Catalonia PMID: 42079620; ~1:12,298 for severe T/B immunodeficiency in Russia PMID: 41727503), but LAT accounts for a tiny fraction of these.

Inheritance: autosomal recessive. Penetrance: complete in biallelic individuals (carriers unaffected). Expressivity: variable — the phenotype ranges from CID-with-autoimmunity to frank T–B+NK+ SCID, even within a single sibship. Anticipation / germline mosaicism / founder effect: none established. Consanguinity: central — all reported families are consanguineous (homozygosity by descent). Carrier frequency: unknown but very low; carriers are healthy. Sex ratio: ~1:1. Populations: reported in consanguineous families (including Arab ancestry) with no established ethnic clustering or founder mutation.

"a severe combined immunodeficiency phenotype with absent T cells and normal B-cell and natural killer cell numbers" — PMID: 27522155 (defines the T–B+NK+ classification underpinning ORPHA:504523)

Section 10 — Diagnostics

Clinical/laboratory tests. Flow cytometry showing reduced/absent T cells with normal B and NK cell numbers (T–B+NK+ pattern); absent T-cell proliferative responses to mitogens/antigens; abnormal immunoglobulins (variably elevated IgG1/IgE with Th2 skewing, or hypogammaglobulinemia); eosinophilia; autoimmune cytopenias (AIHA, ITP) with positive autoantibodies. Functional signaling assays can show absent ERK phosphorylation and preserved Ca²⁺/NF-κB in residual T cells.

Newborn screening. As a cause of T-cell lymphopenia, LAT deficiency is detectable by TREC (T-cell receptor excision circle) quantification on dried blood spots, the standard population screen for SCID (PMID: 42079620; PMID: 41727503; PMID: 42496450).

Genetic testing. Definitive diagnosis is molecular. In reported kindreds this used homozygosity mapping followed by Sanger / whole-exome sequencing (PMID: 27522155; PMID: 37516813). WES/WGS or SCID/CID gene panels including LAT are the recommended approach; single-gene LAT testing is appropriate for cascade testing once a familial variant is known.

"Homozygosity mapping was used to identify potential defective genes" — PMID: 27522155

Differential diagnosis. Other T–B+NK+ SCID (IL7R, CD3D/CD3E/CD3G, PTPRC/CD45, CORO1A); ZAP-70 deficiency; CID with immune dysregulation (IPEX/FOXP3, CTLA4, LRBA, STAT3-GOF, Omenn syndrome); and ALPS for the autoimmune-cytopenia/lymphoproliferation picture.

Section 11 — Outcome / Prognosis

Natural history is severe. Without HSCT, OMIM summarizes that most patients die in childhood. In the index kindred, two of three siblings died (ages 2 and 9); the survivor was transplanted. Mortality is driven by opportunistic/disseminated infection (e.g., CMV) and by acute autoimmune cytopenias.

Prognosis improves markedly with early diagnosis and HSCT. For SCID generally, early (newborn-screening/family-history) diagnosis substantially improves survival:

"The 2-year overall survival (OS) of the late group was 29.2%, in contrast to the 2-year OS of the early diagnosis group of 71.4%" — PMID: 40374985

Morbidity: chronic lung disease/bronchiectasis, autoimmune organ damage, growth/developmental impact from chronic illness, and transplant-related complications. Prognostic factors: age at diagnosis, presence of active infection at HSCT, and degree of immune dysregulation.

Section 12 — Treatment

Curative — allogeneic hematopoietic stem cell transplantation (HSCT) (NCIT: Hematopoietic Cell Transplantation). HSCT is the only curative therapy and replaces the defective hematopoietic/T-lineage compartment.

"Hematopoietic cell transplantation (HCT) is the only curative treatment currently available" — PMID: 40374985

In the index kindred, the proband underwent successful HSCT at age 8 (PMID: 27242165).

Supportive / bridging care (NCIT clinical interventions): - Immunoglobulin replacement therapy (IVIG/SCIG) — NCIT: Immunoglobulin Therapy - Anti-infective prophylaxis — Pneumocystis jirovecii prophylaxis (co-trimoxazole), antivirals, antifungals (PMID: 42496450) - Management of autoimmune cytopenias — corticosteroids/immunosuppression; splenectomy has been used but carries infection risk (one index patient died of disseminated CMV after splenectomy) - Use of irradiated, CMV-safe/leukoreduced blood products; avoidance of live vaccines

Advanced/experimental. No approved gene therapy, gene editing, RNA-based, or targeted therapy exists specifically for LAT deficiency. Mechanistically, IL-6 blockade is a rational candidate for the autoimmune/lymphoproliferative arm given the mouse data (PMID: 26034173), but this is unproven in humans. Pharmacogenomics: not applicable. Personalized medicine: genotype-confirmed diagnosis guides expedited HSCT.

Section 13 — Prevention

Primary prevention: none possible (Mendelian). Secondary prevention: TREC newborn screening enables pre-symptomatic detection and early HSCT — the single most impactful preventive intervention; pre-transplant anti-infective prophylaxis (PJP, antivirals, antifungals) plus IVIG prevents infectious complications; avoidance of live vaccines and use of irradiated/CMV-safe blood products prevent iatrogenic harm. Tertiary prevention: aggressive infection control and management of autoimmune complications. Genetic counseling: autosomal recessive with 25% sibling recurrence risk; carrier testing of relatives, and prenatal or preimplantation genetic diagnosis in families with a known variant. Public health/immunization/environmental measures: not applicable beyond the above.

Section 14 — Other Species / Natural Disease

Taxonomy/orthologs: mouse Lat (NCBI Gene 16797; MGI:1342293; Mus musculus, NCBI Taxon 10090) is the principal ortholog studied; human LAT is NCBI Gene 27040. Natural disease: no naturally occurring LAT deficiency disease is documented in companion animals or wildlife (OMIA has no LAT disease entry as of this review). Comparative biology: the TCR-signalosome role of LAT is evolutionarily conserved across mammals, which is why the mouse recapitulates key disease arms. Zoonotic potential: not applicable (non-infectious genetic disease).

Section 15 — Model Organisms

The mouse has been the decisive model, and two complementary alleles map onto the two arms of human disease:

Model	Allele	Phenotype	Human arm modeled
Complete Lat-null KO	Full loss	Thymocyte development arrested at CD4–CD8– double-negative (DN3) stage; no peripheral T cells	Immunodeficiency
LatY136F knock-in	Tyr136→Phe (PLCγ1 docking site)	Fast-onset polyclonal CD4⁺ Th2 lymphoproliferation, massive IL-4/IgG1/IgE, autoantibodies, nephritis, proteinuria	Autoimmunity / dysregulation
C-terminal 4-tyrosine knock-ins	Multi-Tyr mutants	Reveal LAT's negative-regulatory loss	Homeostatic dysregulation

"Lat(Y136F) mice) develop a fast-onset lymphoproliferative disorder involving polyclonal CD4 T cells that produce massive amounts of Th2 cytokines and trigger severe inflammation and autoantibodies" — PMID: 18209052

"a defect intrinsic to Lat(Y136F) CD4 T cells leads to a state of TCR-independent hyperactivity" — PMID: 18209052

"we observed early-onset systemic autoimmunity with nephritis showing IgE autoantibody deposits and severe proteinuria" — PMID: 16887989

"IL-6 is required for uncontrolled T cell expansion during the early stage of disease development" — PMID: 26034173

Phenotype recapitulation / limitations. No single mouse fully matches the human phenotype: the null models the immunodeficiency arm, Y136F models the autoimmunity arm, but human patients present with a combined, intermediate picture (reduced/residual T cells plus autoimmunity) not captured by either allele alone (PMID: 27242165). Notably, mice show lymphoproliferation whereas human patients show reduced T-cell numbers. Resources: MGI (mouse). No zebrafish/Drosophila/organoid model is established for this disease.

Mechanistic Model / Interpretation

The unifying insight is that LAT is a signaling hub with dual, opposing roles, and losing it simultaneously produces too little useful T-cell signaling (immunodeficiency) and too little restraint on aberrant T-cell activation (autoimmunity):

 biallelic truncating LAT (null)
          │
      ┌───────────┴───────────┐
   POSITIVE role lost         NEGATIVE role lost
   (signalosome absent)       (homeostatic brake gone)
│                             │
  ERK abolished,               TCR-MHC-independent
  Ca²⁺/NFAT impaired            "quasi-mitogenic" Th2
│                       expansion (IL-6-dependent)
  impaired thymic                    │
  selection / activation      polyclonal B activation,
│                     IgG1/IgE, autoantibodies,
  T-lymphopenia,               eosinophilia
  absent proliferation               │
│                     AIHA, ITP, lymphadenopathy,
  recurrent & opportunistic    splenomegaly, nephritis(mouse)
  infections (CMV/VZV/toxo)
│                             │
└────────► COMBINED IMMUNODEFICIENCY ◄────────┘
    + SEVERE AUTOIMMUNITY

This resolves the apparent paradox of a SCID-causing gene that also drives autoimmunity, and it explains the variable expressivity: the balance between residual T-cell output (branch A severity) and unrestrained Th2 activity (branch B severity) shifts along the spectrum from "CID + autoimmunity" to "frank T–B+NK+ SCID." Therapeutically, only replacing the entire compartment (HSCT) addresses both arms, which is why it is the sole curative option.

Evidence Base

PMID	Title (abbrev.)	Contribution
27242165	Early onset combined immunodeficiency and autoimmunity in patients with LOF mutation in LAT	Landmark: first human kindred; defines phenotype, ERK-abolished signaling defect, exon-5 nonsense variant, HSCT outcome
27522155	Mutations in LAT lead to a novel form of SCID	Second kindred; defines T–B+NK+ SCID; frameshift → complete LOF/loss of expression; homozygosity mapping
37516813	8 patients with typical/atypical SCID; 7 novel mutations by WES	Third report; p.Y207fsTer33; confirms recurrent SCID-causing entity, WES diagnosis
18231606	ZAP-70-dependent FRET biosensor	Defines LAT signalosome composition (PLCγ1, Grb2/SOS, GADS, SLP-76)
18209052	Th2 lymphoproliferative disorder of LatY136F mice	Autoimmunity-arm mechanism; T-cell-intrinsic, TCR-independent hyperactivity
16887989	LatY136F triggers polyclonal B activation and systemic autoimmunity	Documents nephritis, IgE autoantibodies, systemic autoimmunity in model
26034173	Importance of IL-6 in LAT-mediated autoimmunity	Identifies IL-6 as driver of early lymphoproliferation
17534068	Th2 lymphoproliferation from defective LAT signalosomes	Establishes LAT's negative-regulatory role
16102570	Role of LAT in T-cell development and Th2 differentiation	Multi-lineage LAT expression; null → thymic block
40374985	Newborn screening improves survival in SCID	Quantifies early- vs late-diagnosis survival; HSCT curative
42079620 / 41727503 / 42496450	SCID newborn-screening programs	TREC/KREC screening context and diagnostic workflow

Evidence quality. The human disease rests on case reports of ≤3 independent consanguineous kindreds (low n but concordant and mechanistically coherent). Mechanism is strongly supported by mouse genetics and in vitro signaling studies. Prognosis/screening/treatment claims are extrapolated from the broader SCID literature, which is robust.

Limitations and Knowledge Gaps

Very small human N (<20 patients). Prevalence, penetrance nuances, full phenotypic range, and genotype–phenotype correlations are provisional.
No LAT-specific outcome data. Survival/HSCT-outcome figures are borrowed from general SCID cohorts, not LAT-specific series.
Branch B (autoimmunity) mechanism is inferred from mouse. The IL-6 dependence and "quasi-mitogenic" Th2 model are demonstrated in LatY136F mice; direct human confirmation is limited.
Model mismatch. No single mouse reproduces the combined human phenotype (humans have reduced T cells; Y136F mice have lymphoproliferation).
No human variant catalog beyond truncating alleles. Missense/hypomorphic human alleles and their consequences are unknown; no VUS spectrum defined.
Non-T lineage contribution (mast cells, NK, platelets, early B cells) is uncharacterized in patients.
No naturally occurring animal disease documented (OMIA gap).

Proposed Follow-up Experiments / Actions

Establish an international LAT-deficiency registry to pool the scattered kindreds and capture natural history, HSCT outcomes, and genotype–phenotype data.
Deep immunophenotyping of patients (single-cell RNA-seq / CITE-seq of residual T cells) to test whether the human Th2-skewing/negative-regulation mechanism mirrors the mouse and to define which cell states drive autoimmunity.
Test IL-6 pathway blockade (e.g., tocilizumab) as a bridge-to-transplant for the autoimmune/lymphoproliferative arm, given the mouse IL-6 dependence (PMID: 26034173).
Assess non-T lineage function (platelet GPVI signaling, mast cell, NK activity) in patients, since LAT is expressed in these lineages.
Generate a humanized or hypomorphic-allele mouse / patient iPSC-derived thymic organoid that recapitulates the combined (reduced-T-cell + autoimmunity) human phenotype for preclinical testing.
Explore gene-corrected autologous HSC therapy (lentiviral LAT or base/prime editing) as a future alternative to allogeneic HSCT, mindful that LAT expression must be tightly regulated to avoid recreating dysregulation.
Ensure LAT is included in confirmatory SCID gene panels downstream of TREC-positive newborn screens so that these patients are captured early.

Report compiled from 10 confirmed findings and 22 reviewed papers over 5 investigation iterations. Evidence types: human clinical case reports (Keller 2016, Bacchelli 2017, Alizadeh 2023); mouse model organism studies (LatY136F, Lat-null); in vitro signaling studies; and SCID newborn-screening epidemiology.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome	Count
References checked	13
Resolved	13
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	13
On topic	11
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	38
Resolved	35
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	3
Terms whose name was checked	32
Terms named correctly	15
Terms named as a different term	10
Terms whose name is worth a second look	7

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0044721 (2 mentions) - the report calls it "MONDO"; MONDO calls it severe combined immunodeficiency due to LAT deficiency
HP:0004810 (1 mention) - the report calls it "Lab/clinical"; HP calls it Congenital hypoplastic anemia
HP:0001973 (1 mention) - the report calls it "Lab/clinical"; HP calls it Autoimmune thrombocytopenia
HP:0002716 (1 mention) - the report calls it "Physical sign"; HP calls it Lymphadenopathy
HP:0002110 (1 mention) - the report calls it "Physical sign"; HP calls it Bronchiectasis
HP:0011355 (1 mention) - the report calls it "Physical manifestation"; HP calls it Localized skin lesion
HP:0005403 (1 mention) - the report calls it "Lab abnormality"; HP calls it Decreased total T cell count
HP:0001880 (1 mention) - the report calls it "Lab abnormality"; HP calls it Increased total eosinophil count
HP:0003212 (1 mention) - the report calls it "Lab abnormality"; HP calls it Increased circulating IgE concentration
HP:0002720 (1 mention) - the report calls it "Lab abnormality"; HP calls it Decreased circulating IgA concentration

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0070374 (1 mention) - the report calls it "positive regulation of ERK cascade"; GO calls it positive regulation of ERK1 and ERK2 cascade, and lists "positive regulation of ERK cascade" among its other names
CL:0000624 (2 mentions) - the report calls it "CD4+ T cell"; CL calls it CD4-positive, alpha-beta T cell
CL:0000623 (1 mention) - the report calls it "NK cell"; CL calls it natural killer cell, and lists "NK cell" among its other names
UBERON:0002405 (1 mention) - the report calls it "Primary — immune/hematopoietic system"; UBERON calls it immune system
UBERON:0000178 (1 mention) - the report calls it "Peripheral blood"; UBERON calls it blood, and lists "vertebrate blood" among its other names
UBERON:0002097 (1 mention) - the report calls it "Skin"; UBERON calls it skin of body, and lists "skin" among its other names
UBERON:0000160 (1 mention) - the report calls it "Gastrointestinal tract"; UBERON calls it intestine, and lists "intestinal tract" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.

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Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Animal Models

Source YAML

References & Deep Research

References

Deep Research

LAT Deficiency (Immunodeficiency-52): A Comprehensive Disease Characterization

Summary

Section 1 — Disease Information

Section 2 — Etiology

Section 3 — Phenotypes

Section 4 — Genetic / Molecular Information

Section 5 — Environmental Information

Section 6 — Mechanism / Pathophysiology

Ordered causal chain

Signalosome schematic

Section 7 — Anatomical Structures Affected

Section 8 — Temporal Development

Section 9 — Inheritance and Population

Section 10 — Diagnostics

Section 11 — Outcome / Prognosis

Section 12 — Treatment

Section 13 — Prevention

Section 14 — Other Species / Natural Disease

Section 15 — Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver