DEF6 Deficiency

Mendelian MONDO:0030457 Pathograph 16 Show in embeddings browser Primary Immunodeficiency

An autosomal recessive inborn error of immunity caused by biallelic loss of DEF6, a guanine nucleotide exchange factor. DEF6 binds the small GTPase RAB11 and is required for delivery of the checkpoint receptor CTLA-4 from its intracellular vesicle pool to the T-cell surface. Losing it produces a functional CTLA-4 insufficiency: regulatory T cells cannot mobilise enough surface CTLA-4 to restrain co-stimulation, and patients develop early-onset systemic autoimmunity, lymphoproliferation, and — in the second reported family — chronic EBV viraemia and EBV-driven lymphoma. Because the lesion is a shortage of available CTLA-4 rather than of the protein itself, CTLA-4-Ig (abatacept) is a mechanistically direct replacement therapy, and the one patient treated with it achieved sustained remission. The entire human evidence base is seven patients from three kindreds in two reports, and two of the three patients in the first report also carried a homozygous pathogenic SKIV2L variant, so some of the originally described extrahaematologic phenotype may not be attributable to DEF6. See the discussions section.

Ask OpenScientist

Ask a research question about DEF6 Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
9
Pathophys.
6
Phenotypes
2
Gaps
16
Pathograph
1
Genes
5
Medical Actions
1
Models
1
Deep Research
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC GENETICS ENVIRONMENT DISEASE
IUIS Category
immune dysregulation
👪

Inheritance

1
Autosomal recessive HP:0000007
Both reports describe biallelic (homozygous) DEF6 variants. In the second family Sanger sequencing confirmed homozygosity in all four affected siblings of a consanguineous kindred while both parents were heterozygous and unaffected.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:31308374 SUPPORT Human Clinical
"we identify biallelic mutations in three patients from two unrelated families"
Biallelic variants in affected individuals from unrelated families indicate recessive inheritance.
?

Discussions and Knowledge Gaps

2
Which features of the originally reported DEF6 phenotype are attributable to DEF6 and which to the co-occurring SKIV2L variant?
KNOWLEDGE GAP def6_skiv2l_confound
Attached to
pathophysiology#Biallelic DEF6 Loss of Function disease#DEF6 Deficiency
Two of the three patients in the index report also carried a homozygous predicted-pathogenic SKIV2L variant. SKIV2L deficiency causes trichohepatoenteric syndrome, whose features — intractable diarrhoea, liver disease, developmental abnormality and combined immunodeficiency — overlap substantially with the severe digestive and cardiac involvement described in those patients. The second report makes this point explicitly and describes a four-sibling family with no other pathogenic variant detected, in whom the phenotype is autoimmunity and EBV susceptibility without the extrahaematologic features. Until more unconfounded patients are reported, the digestive and cardiac manifestations should not be treated as established DEF6 phenotypes, and the same applies to the severe bacterial and respiratory infections, which the second report also localises to the SKIV2L carriers. The phenotypes section is scoped accordingly.
Show evidence (2 references)
PMID:32562707 SUPPORT Human Clinical
"However, 2 of the 3 patients were also carrying a predicted pathogenic homozygous variant in SKIV2L"
Documents the co-occurring SKIV2L variant in the index cohort.
PMID:31308374 SUPPORT Human Clinical
"could represent a disease-modifying factor potentially affecting cardiac function"
The index authors reach the same conclusion independently, treating the SKIV2L variant as a disease modifier for the cardiac and bowel features while holding that it does not explain the autoimmune presentation. Both reports agreeing is what makes the confound a settled caveat rather than one group's critique of another.
What is the effector defect that makes DEF6-deficient patients unable to control EBV, and is it downstream of the CTLA-4 trafficking lesion at all?
KNOWLEDGE GAP def6_ebv_effector_defect
Attached to
pathophysiology#Impaired Control of Epstein-Barr Virus
EBV susceptibility and EBV-driven lymphoma were the presenting features of the second family but were not described in the index report, where the CTLA-4 trafficking mechanism was worked out. Reduced surface CTLA-4 explains loss of tolerance, but it is not an obvious explanation for failed antiviral control, which usually reflects a cytotoxic T-cell or NK-cell defect. Whether the two arms share a mechanism or DEF6 has a separate role in cytotoxic lymphocyte function is unresolved, and no experiment in either report addresses it.
⚙

Pathophysiology

9
Biallelic DEF6 Loss of Function
Biallelic DEF6 variants abolish or cripple the guanine nucleotide exchange factor. Two mechanisms are documented: homozygous missense variants that leave protein expression strongly reduced (index report), and a homozygous nonsense variant (c.940C>T, p.Gln314Ter) that behaves as a null allele with complete loss of detectable DEF6 in patient T-cell blasts (second family).
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
DEF6 hgnc:2760 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DEF6 (hgnc:2760). hgnc:2760 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Disrupted RAB11-Dependent CTLA-4 Vesicle Trafficking Loss of DEF6 removes the RAB11 interaction required to load CTLA-4 into recycling vesicles.
Show evidence (1 reference)
PMID:31308374 SUPPORT Human Clinical
"we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity"
Establishes biallelic DEF6 loss as the molecular cause of the disorder.
Disrupted RAB11-Dependent CTLA-4 Vesicle Trafficking
DEF6 interacts with the small GTPase RAB11, which governs the recycling endosome. Mutant DEF6 shows disrupted binding to RAB11, and DEF6-mutated cells contain fewer RAB11-positive, CTLA-4-positive vesicles. The lesion is therefore in the delivery machinery for CTLA-4, not in CTLA-4 itself — the same failure point that LRBA deficiency reaches by a different route.
regulatory T cell CL:0000815 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves regulatory T cell (CL:0000815). CL:0000815 is a cell type from the Cell Ontology.
vesicle-mediated transport GO:0016192 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased vesicle-mediated transport (GO:0016192). GO:0016192 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced Surface CTLA-4 Availability Fewer CTLA-4-loaded recycling vesicles reach the plasma membrane, lowering surface CTLA-4.
Show evidence (2 references)
PMID:31308374 SUPPORT In Vitro
"we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11+CTLA-4+ vesicles in DEF6-mutated cells"
Establishes the RAB11 interaction and its disruption as the trafficking defect.
PMID:41158012 SUPPORT Other
"Recent studies highlight the importance of LRBA/DEF6-mediated CTLA-4 recycling to maintain immune tolerance."
Independent review placing DEF6 in the CTLA-4 recycling machinery alongside LRBA.
Reduced Surface CTLA-4 Availability
Patient T cells show impaired regulation of CTLA-4 surface trafficking and reduced functional CTLA-4 availability, a phenotype reproduced in DEF6-knockout Jurkat cells. This is a functional CTLA-4 insufficiency arising from a normal CTLA4 locus, which is why the disorder is clinically grouped with CTLA-4 insufficiency and LRBA deficiency despite having a different causal gene.
regulatory T cell CL:0000815 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves regulatory T cell (CL:0000815). CL:0000815 is a cell type from the Cell Ontology.
Experimental models
DEF6-knockout Jurkat T-cell line CELL LINE The knockout line reproduces the impaired CTLA-4 surface trafficking seen in patient T cells.
Downstream
Defective Regulatory T Cell Suppression CTLA-4 is the effector molecule of Treg-mediated suppression; less surface CTLA-4 means less suppression.
Show evidence (1 reference)
PMID:31308374 SUPPORT In Vitro
"Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells."
Establishes reduced functional surface CTLA-4 in patient cells and its reproduction in a knockout cell line. Graded IN_VITRO because both halves are assays on cultured cells - patient T cells ex vivo and a knockout line - not an in-vivo clinical observation.
Defective Regulatory T Cell Suppression
With insufficient surface CTLA-4, regulatory T cells cannot compete for and transendocytose B7 ligands from antigen-presenting cells, so co-stimulation of conventional T cells goes unrestrained. This is the shared final common step of the CTLA-4/LRBA/DEF6 group of immune-dysregulation disorders.
regulatory T cell CL:0000815 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves regulatory T cell (CL:0000815). CL:0000815 is a cell type from the Cell Ontology.
negative regulation of T cell activation GO:0050868 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of T cell activation (GO:0050868). GO:0050868 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Systemic Autoimmunity Unrestrained T-cell activation drives multi-organ autoimmunity, prominently autoimmune cytopenias.
Impaired Class-Switched B Cell Compartment Loss of regulated T-cell help disturbs germinal centre output, leaving a reduced class-switched memory B-cell compartment.
Lymphoproliferation Loss of the CTLA-4 brake also permits uncontrolled lymphocyte expansion.
Impaired Control of Epstein-Barr Virus Immune dysregulation extends to failure of EBV control, though the precise effector defect responsible has not been resolved.
Show evidence (1 reference)
PMID:33996698 SUPPORT Other
"mainly attributed to a defective suppressive activity of Tregs, as all three diseases reduce overall surface expression of CTLA-4"
Attributes the shared phenotype to defective Treg suppression secondary to reduced surface CTLA-4.
Impaired Class-Switched B Cell Compartment
Reduced class-switched B cells alongside T-cell lymphopenia in the index cohort. This is the humoral arm of the disease and is what immunoglobulin substitution is actually directed at — it is distinct from the autoimmunity, which replacement-dose immunoglobulin does not treat.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
Show evidence (1 reference)
PMID:31308374 SUPPORT Human Clinical
"Clinical and immunological phenotypes in DEF6-mutated patients include T-cell lymphopenia, low class-switched B cells"
Records the reduced class-switched B-cell compartment among the immunological phenotypes of DEF6-mutated patients.
Systemic Autoimmunity
The dominant clinical arm: early-onset multi-organ autoimmunity, prominently autoimmune cytopenias. Autoantibodies were detectable in three of four siblings in the second family, and the youngest developed severe autoimmune haemolytic anaemia and thrombocytopenia in the first year of life.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
Show evidence (1 reference)
PMID:31308374 SUPPORT Human Clinical
"as the molecular cause of an inborn error of immunity with systemic autoimmunity"
Systemic autoimmunity is the defining clinical consequence in the index cohort.
Lymphoproliferation
Uncontrolled lymphocyte expansion presenting as lymphadenopathy, hepatosplenomegaly and, when EBV-driven, frank lymphoproliferative disease. It has two upstream sources in this disease that are worth keeping separate: loss of the CTLA-4 brake on lymphocyte activation, and failure to control EBV in B cells.
lymphocyte CL:0000542 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves lymphocyte (CL:0000542). CL:0000542 is a cell type from the Cell Ontology.
Downstream
EBV-Driven Lymphoproliferative Disease Lymphoproliferation in the presence of uncontrolled EBV creates the substrate for EBV-positive lymphoma.
Show evidence (1 reference)
PMID:33996698 SUPPORT Other
"Patients characteristically present with an increased risk of infections, autoimmune cytopenias, multi-organ autoimmunity, and inflammation, which are often severe and life-threatening."
Establishes lymphoproliferative and inflammatory disease as characteristic of this disease group.
EBV-Driven Lymphoproliferative Disease
The terminal event of the EBV arm: recurrent EBV-positive lymphoproliferation and, in the proband of the second family, EBV-positive nodular sclerosis classic Hodgkin lymphoma at age 10, treated with autologous stem cell transplantation and followed by further episodes at persistently high EBV loads.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
Show evidence (1 reference)
PMID:32562707 SUPPORT Human Clinical
"the index case patient (patient 2) experienced an EBV - positive nodular sclerosis classic Hodgkin lymphoma (HL)"
Documents EBV-driven Hodgkin lymphoma as the terminal event of this arm.
Impaired Control of Epstein-Barr Virus
The second reported family established a distinct arm not evident in the index report: chronic high-level EBV viraemia and EBV-driven lymphoproliferation, including EBV-positive nodular sclerosis classic Hodgkin lymphoma in the proband. This is why the second report titled the condition a mendelian susceptibility to EBV infection.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
Downstream
EBV-Driven Lymphoproliferative Disease Failure to control EBV in B cells is what makes the lymphoproliferation EBV-positive and drives it toward lymphoma.
Show evidence (2 references)
PMID:32562707 SUPPORT Human Clinical
"patients 1 and 3 also showed abnormal detectable blood EBV loads (>4 log copies/mL) over 6 months"
Documents sustained high EBV viral loads in affected siblings.
PMID:32562707 SUPPORT Human Clinical
"the index case patient (patient 2) experienced an EBV - positive nodular sclerosis classic Hodgkin lymphoma (HL)"
Documents EBV-driven Hodgkin lymphoma in the proband of the second family.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for DEF6 Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Blood 2
Autoimmune cytopenia FREQUENT Autoimmune hemolytic anemia HP:0001890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmune hemolytic anemia (HP:0001890). HP:0001890 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33996698 SUPPORT Other
"Patients characteristically present with an increased risk of infections, autoimmune cytopenias, multi-organ autoimmunity, and inflammation, which are often severe and life-threatening."
Autoimmune cytopenias are a characteristic presenting feature of this disease group.
Lymphoma OCCASIONAL HP:0002665 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphoma (HP:0002665). HP:0002665 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32562707 SUPPORT Human Clinical
"the index case patient (patient 2) experienced an EBV - positive nodular sclerosis classic Hodgkin lymphoma (HL)"
Documents lymphoma in a DEF6-deficient patient.
PMID:33996698 SUPPORT Other
"these patients suffer an increased risk of developing malignancies, especially Non-Hodgkin's lymphoma"
Establishes elevated lymphoma risk across the CTLA-4/LRBA/DEF6 group.
Cardiovascular 2
Lymphadenopathy OCCASIONAL HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32562707 SUPPORT Human Clinical
"recently developed cervical lymph node enlargement with spontaneous regression"
Directly documents lymph node enlargement in the eldest affected sibling.
Hepatosplenomegaly OCCASIONAL HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31308374 SUPPORT Human Clinical
"Clinical and immunological phenotypes in DEF6-mutated patients include T-cell lymphopenia, low class-switched B cells, hepatosplenomegaly, autoimmune hemolytic anemia"
Listed among the clinical phenotypes of DEF6-mutated patients in the index report. Graded PARTIAL because that cohort includes the two SKIV2L carriers and the report does not resolve the finding per patient.
Other 2
Susceptibility to Epstein-Barr virus and cytomegalovirus FREQUENT Recurrent viral infections HP:0004429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Susceptibility to viral infection, annotated with Recurrent viral infections (HP:0004429). HP:0004429 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32562707 SUPPORT Human Clinical
"The 4 patients reported here did not have cardiac or digestive abnormalities and did not experience severe or opportunistic infections (except EBV). In Serwas et al ,4 all of these symptoms were restricted to both carriers of an additional SKIV2L variant"
Restricts the infection phenotype to EBV in the unconfounded family and attributes the broader infection susceptibility to the SKIV2L carriers, which is why this phenotype is scoped to EBV and CMV.
PMID:32562707 SUPPORT Human Clinical
"Except for CMV in patient 4, there was no evidence for other viral infection"
Carries the CMV half of this phenotype explicitly, and simultaneously excludes any other viral susceptibility in the unconfounded family.
Persistent EBV viremia FREQUENT HP:0020072 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is persistent Epstein-Barr virus viremia, annotated with Persistent EBV viremia (HP:0020072). HP:0020072 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32562707 SUPPORT Human Clinical
"patients 1 and 3 also showed abnormal detectable blood EBV loads (>4 log copies/mL) over 6 months"
Documents sustained high-level EBV viraemia in affected siblings.
🧬

Genetic Associations

1
DEF6 (Causative)
Gene: DEF6 hgnc:2760 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DEF6 (hgnc:2760). hgnc:2760 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:31308374 SUPPORT Human Clinical
"we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity"
Identifies DEF6 as the causative gene.
💊

Medical Actions

5
Abatacept (CTLA-4-Ig)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: abatacept NCIT:C28898 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses abatacept (NCIT:C28898). NCIT:C28898 is a therapeutic agent from the NCI Thesaurus.
A soluble CTLA-4-Ig fusion protein that supplies extracellularly the B7-binding function the patient's T cells cannot deliver to their own surface — a direct pharmacological substitution for the trafficking defect. One patient in the index report achieved sustained remission on it. The evidence for this disease is therefore a single treated patient, and the supporting review evidence is extrapolated from the larger CTLA-4 insufficiency and LRBA deficiency cohorts.
Mechanism Target:
BYPASSES Defective Regulatory T Cell Suppression — Soluble CTLA-4-Ig binds B7 ligands directly, restoring the co-stimulatory blockade that surface-CTLA-4-deficient Tregs cannot impose.
Show evidence (2 references)
PMID:31308374 SUPPORT Human Clinical
"One of the patients has been treated with CTLA-4-Ig and achieved sustained remission."
The single reported treatment response in DEF6 deficiency.
PMID:33996698 SUPPORT Other
"Successful treatment options include regular administration of soluble CTLA-4-Ig fusion protein, Treg cell-sparing immune suppressants like sirolimus or mycophenolate mofetil, and hematopoietic stem cell transplantation."
Review-level support for CTLA-4-Ig, but stated for the CTLA-4/LRBA/DEF6 group as a whole rather than for DEF6 deficiency specifically.
Hematopoietic stem cell transplantation
Action: hematopoietic cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hematopoietic cell transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Allogeneic HSCT is the only potentially curative option in this group of immune-dysregulation disorders. No DEF6-specific transplant outcome series exists; the recommendation is extrapolated from CTLA-4 insufficiency and LRBA deficiency.
Mechanism Target:
BYPASSES Biallelic DEF6 Loss of Function — Donor engraftment supplies DEF6-competent lymphocytes; it does not correct the patient's own DEF6 alleles, which is why this is a bypass rather than a restoration of the node as named.
Show evidence (1 reference)
PMID:41158012 SUPPORT Other
"hematopoietic stem cell transplantation (HSCT) remains the only curative option"
Review states HSCT is the only curative option for the CTLA4-related disorders; DEF6-specific transplant evidence is absent.
Immunoglobulin replacement
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Regular immunoglobulin substitution, documented in the index report's first patient, in whom recurrent infections requiring antibiotics persisted alongside it. That patient is one of the two SKIV2L carriers, so this is supportive rather than established practice for DEF6 deficiency specifically.
Mechanism Target:
BYPASSES Impaired Class-Switched B Cell Compartment — Substituting immunoglobulin supplies the antibody the impaired class-switched compartment cannot, without addressing the CTLA-4 trafficking lesion behind it. It is directed at the humoral deficit, not at the autoimmunity - replacement-dose immunoglobulin is not the high-dose immunomodulatory intervention.
Show evidence (1 reference)
PMID:31308374 SUPPORT Human Clinical
"Regular immunoglobulin treatment is given. Recurrent infections requiring antibiotic treatment have persisted"
Documents immunoglobulin substitution in the index report's first patient. Graded PARTIAL because that patient also carried the SKIV2L variant, so the indication cannot be attributed to DEF6 alone.
Treg-sparing immunosuppression (sirolimus, mycophenolate mofetil)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sirolimus CHEBI:9168 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sirolimus (CHEBI:9168). CHEBI:9168 is a therapeutic agent from Chemical Entities of Biological Interest. mycophenolate mofetil CHEBI:8764 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses mycophenolate mofetil (CHEBI:8764). CHEBI:8764 is a therapeutic agent from Chemical Entities of Biological Interest.
Immunosuppressants chosen to spare the regulatory T-cell compartment, which is already functionally impaired by the CTLA-4 shortage. As with abatacept and HSCT, the recommendation is made for the CTLA-4 / LRBA / DEF6 group as a whole rather than for DEF6 deficiency specifically.
Mechanism Target:
INHIBITS Systemic Autoimmunity — Suppresses the effector arm of the autoimmunity while sparing the residual regulatory T-cell compartment.
Show evidence (1 reference)
PMID:33996698 SUPPORT Other
"Successful treatment options include regular administration of soluble CTLA-4-Ig fusion protein, Treg cell-sparing immune suppressants like sirolimus or mycophenolate mofetil, and hematopoietic stem cell transplantation."
Review-level support for Treg-sparing immunosuppression, stated for the CTLA-4/LRBA/DEF6 group rather than for DEF6 deficiency alone.
Second-line immunosuppression for refractory autoimmune cytopenia
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
In the youngest sibling of the unconfounded family, severe autoimmune haemolytic anaemia and thrombocytopenia were treated with corticosteroids, rituximab, azathioprine and bortezomib together with plasma exchange. The report describes the response as only moderate, which is the informative part: conventional escalation does not control the cytopenias well in this disease, and that is the argument for going to mechanism-directed CTLA-4-Ig or to transplant.
Mechanism Target:
INHIBITS Systemic Autoimmunity — Broad immunosuppression and antibody removal directed at the autoimmune cytopenia rather than at its cause.
Show evidence (1 reference)
PMID:32562707 SUPPORT Human Clinical
"Treatment involving administration of corticosteroids, rituximab, azathioprine"
Records the second-line regimen used for refractory autoimmune cytopenia in this patient. Graded PARTIAL because the same sentence reports only moderate efficacy.
📊

Prevalence

1
Worldwide
Cases In Literature <1 in 1,000,000
Seven patients from three kindreds have been reported: three patients from two unrelated families in the index report, and four affected siblings of a single consanguineous family in the second. No population prevalence estimate exists.
Show evidence (1 reference)
PMID:31308374 SUPPORT Human Clinical
"we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6)"
Establishes the size and family structure of the index cohort.
🧫

Experimental Models

1
DEF6-knockout Jurkat T-cell line CELL_LINE
A DEF6-knockout human T-cell line generated in the index report. It is the strongest causality evidence in the disease: the patient CTLA-4 trafficking defect is reproduced in cells whose only relevant difference is the absence of DEF6, which rules out the patient-specific confounders (including the SKIV2L variant carried by two of the three index patients) that the observational data cannot.
Pathograph links
Reduced Surface CTLA-4 Availability recapitulates fidelity: moderate The knockout line reproduces the impaired CTLA-4 surface trafficking seen in patient T cells.
Limitations: Jurkat is a transformed leukaemic line, not a primary regulatory T cell, so it models the trafficking machinery rather than Treg suppressive function, and it cannot speak to the organism-level autoimmunity.
Readouts
Surface CTLA-4 availability on stimulated T cells
Direction: DECREASED
Interpretation: Reduced functional CTLA-4 at the cell surface is the measurement that makes this line informative for the node.
Show evidence (1 reference)
PMID:31308374 SUPPORT In Vitro
"which is replicated in DEF6-knockout Jurkat cells"
The knockout line reproduces the reduced surface CTLA-4 measured in patient T cells.
Show evidence (1 reference)
PMID:31308374 SUPPORT In Vitro
"which is replicated in DEF6-knockout Jurkat cells"
States that the patient CTLA-4 trafficking phenotype is reproduced in the knockout line.
Show evidence (1 reference)
PMID:31308374 SUPPORT In Vitro
"Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells."
Establishes the knockout line as an informative model of the CTLA-4 trafficking defect.
{ }

Source YAML

click to show 
name: DEF6 Deficiency
creation_date: "2026-08-27T16:00:00Z"
category: Mendelian
synonyms:
- immunodeficiency 87 and autoimmunity
- IMD87
- immunodeficiency due to DEF6 deficiency
disease_term:
  preferred_term: DEF6 deficiency
  term:
    id: MONDO:0030457
    label: immunodeficiency 87 and autoimmunity
parents:
- Primary Immunodeficiency
description: >-
  An autosomal recessive inborn error of immunity caused by biallelic loss of
  DEF6, a guanine nucleotide exchange factor. DEF6 binds the small GTPase RAB11
  and is required for delivery of the checkpoint receptor CTLA-4 from its
  intracellular vesicle pool to the T-cell surface. Losing it produces a
  functional CTLA-4 insufficiency: regulatory T cells cannot mobilise enough
  surface CTLA-4 to restrain co-stimulation, and patients develop early-onset
  systemic autoimmunity, lymphoproliferation, and — in the second reported
  family — chronic EBV viraemia and EBV-driven lymphoma. Because the lesion is
  a shortage of available CTLA-4 rather than of the protein itself, CTLA-4-Ig
  (abatacept) is a mechanistically direct replacement therapy, and the one
  patient treated with it achieved sustained remission.

  The entire human evidence base is seven patients from three kindreds in two
  reports, and two of the three patients in the first report also carried a
  homozygous pathogenic SKIV2L variant, so some of the originally described
  extrahaematologic phenotype may not be attributable to DEF6. See the
  discussions section.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:31308374
      reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "as the molecular cause of an inborn error of immunity with systemic autoimmunity"
      explanation: DEF6 deficiency is an inborn error of immunity presenting with systemic autoimmunity, placing it in Harrison's immune/rheumatologic Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:31308374
      reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6)"
      explanation: A single-gene biallelic Mendelian disorder, supporting placement in Harrison's genetics Part.
  iuis_category:
    classification_value: immune dysregulation
    evidence:
    - reference: PMID:33996698
      reference_title: "Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Therefore, patients with CTLA-4 insufficiency, LRBA deficiency, and-most recently reported-DEF6 deficiency present an overlapping clinical phenotype mainly attributed to a defective suppressive activity of Tregs"
      explanation: DEF6 deficiency is grouped with the CTLA-4/LRBA immune-dysregulation disorders on the basis of defective Treg suppression.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Seven patients from three kindreds have been reported: three patients from
    two unrelated families in the index report, and four affected siblings of a
    single consanguineous family in the second. No population prevalence
    estimate exists.
  evidence:
  - reference: PMID:31308374
    reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6)"
    explanation: Establishes the size and family structure of the index cohort.
pathophysiology:
- name: Biallelic DEF6 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic DEF6 variants abolish or cripple the guanine nucleotide exchange
    factor. Two mechanisms are documented: homozygous missense variants that
    leave protein expression strongly reduced (index report), and a homozygous
    nonsense variant (c.940C>T, p.Gln314Ter) that behaves as a null allele with
    complete loss of detectable DEF6 in patient T-cell blasts (second family).
  genes:
  - preferred_term: DEF6
    term:
      id: hgnc:2760
      label: DEF6
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:31308374
    reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity"
    explanation: Establishes biallelic DEF6 loss as the molecular cause of the disorder.
  downstream:
  - target: Disrupted RAB11-Dependent CTLA-4 Vesicle Trafficking
    causal_link_type: DIRECT
    description: Loss of DEF6 removes the RAB11 interaction required to load CTLA-4 into recycling vesicles.
- name: Disrupted RAB11-Dependent CTLA-4 Vesicle Trafficking
  biological_scale: CELLULAR
  description: >-
    DEF6 interacts with the small GTPase RAB11, which governs the recycling
    endosome. Mutant DEF6 shows disrupted binding to RAB11, and DEF6-mutated
    cells contain fewer RAB11-positive, CTLA-4-positive vesicles. The lesion is
    therefore in the delivery machinery for CTLA-4, not in CTLA-4 itself — the
    same failure point that LRBA deficiency reaches by a different route.
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  biological_processes:
  - preferred_term: vesicle-mediated transport
    term:
      id: GO:0016192
      label: vesicle-mediated transport
    modifier: DECREASED
  evidence:
  - reference: PMID:31308374
    reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11+CTLA-4+ vesicles in DEF6-mutated cells"
    explanation: Establishes the RAB11 interaction and its disruption as the trafficking defect.
  - reference: PMID:41158012
    reference_title: "CTLA4-related primary immune dysregulatory disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recent studies highlight the importance of LRBA/DEF6-mediated CTLA-4 recycling to maintain immune tolerance."
    explanation: Independent review placing DEF6 in the CTLA-4 recycling machinery alongside LRBA.
  downstream:
  - target: Reduced Surface CTLA-4 Availability
    causal_link_type: DIRECT
    description: Fewer CTLA-4-loaded recycling vesicles reach the plasma membrane, lowering surface CTLA-4.
- name: Reduced Surface CTLA-4 Availability
  biological_scale: CELLULAR
  description: >-
    Patient T cells show impaired regulation of CTLA-4 surface trafficking and
    reduced functional CTLA-4 availability, a phenotype reproduced in
    DEF6-knockout Jurkat cells. This is a functional CTLA-4 insufficiency
    arising from a normal CTLA4 locus, which is why the disorder is clinically
    grouped with CTLA-4 insufficiency and LRBA deficiency despite having a
    different causal gene.
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  evidence:
  - reference: PMID:31308374
    reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells."
    explanation: >-
      Establishes reduced functional surface CTLA-4 in patient cells and its
      reproduction in a knockout cell line. Graded IN_VITRO because both halves
      are assays on cultured cells - patient T cells ex vivo and a knockout line
      - not an in-vivo clinical observation.
  downstream:
  - target: Defective Regulatory T Cell Suppression
    causal_link_type: DIRECT
    description: CTLA-4 is the effector molecule of Treg-mediated suppression; less surface CTLA-4 means less suppression.
- name: Defective Regulatory T Cell Suppression
  biological_scale: CELLULAR
  description: >-
    With insufficient surface CTLA-4, regulatory T cells cannot compete for and
    transendocytose B7 ligands from antigen-presenting cells, so co-stimulation
    of conventional T cells goes unrestrained. This is the shared final common
    step of the CTLA-4/LRBA/DEF6 group of immune-dysregulation disorders.
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  biological_processes:
  - preferred_term: negative regulation of T cell activation
    term:
      id: GO:0050868
      label: negative regulation of T cell activation
    modifier: DECREASED
  evidence:
  - reference: PMID:33996698
    reference_title: "Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "mainly attributed to a defective suppressive activity of Tregs, as all three diseases reduce overall surface expression of CTLA-4"
    explanation: Attributes the shared phenotype to defective Treg suppression secondary to reduced surface CTLA-4.
  downstream:
  - target: Systemic Autoimmunity
    causal_link_type: DIRECT
    description: Unrestrained T-cell activation drives multi-organ autoimmunity, prominently autoimmune cytopenias.
  - target: Impaired Class-Switched B Cell Compartment
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - disturbed T-cell help to germinal centre B cells
    description: >-
      Loss of regulated T-cell help disturbs germinal centre output, leaving a
      reduced class-switched memory B-cell compartment.
  - target: Lymphoproliferation
    causal_link_type: DIRECT
    description: Loss of the CTLA-4 brake also permits uncontrolled lymphocyte expansion.
  - target: Impaired Control of Epstein-Barr Virus
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - dysregulated cytotoxic T-cell and NK-cell responses to EBV-infected B cells
    description: >-
      Immune dysregulation extends to failure of EBV control, though the precise
      effector defect responsible has not been resolved.
- name: Impaired Class-Switched B Cell Compartment
  biological_scale: CELLULAR
  description: >-
    Reduced class-switched B cells alongside T-cell lymphopenia in the index
    cohort. This is the humoral arm of the disease and is what immunoglobulin
    substitution is actually directed at — it is distinct from the autoimmunity,
    which replacement-dose immunoglobulin does not treat.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:31308374
    reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical and immunological phenotypes in DEF6-mutated\npatients include T-cell lymphopenia, low class-switched B cells"
    explanation: Records the reduced class-switched B-cell compartment among the immunological phenotypes of DEF6-mutated patients.
- name: Systemic Autoimmunity
  biological_scale: ORGANISM
  description: >-
    The dominant clinical arm: early-onset multi-organ autoimmunity, prominently
    autoimmune cytopenias. Autoantibodies were detectable in three of four
    siblings in the second family, and the youngest developed severe autoimmune
    haemolytic anaemia and thrombocytopenia in the first year of life.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:31308374
    reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as the molecular cause of an inborn error of immunity with systemic autoimmunity"
    explanation: Systemic autoimmunity is the defining clinical consequence in the index cohort.
- name: Lymphoproliferation
  biological_scale: ORGANISM
  description: >-
    Uncontrolled lymphocyte expansion presenting as lymphadenopathy,
    hepatosplenomegaly and, when EBV-driven, frank lymphoproliferative disease.
    It has two upstream sources in this disease that are worth keeping separate:
    loss of the CTLA-4 brake on lymphocyte activation, and failure to control
    EBV in B cells.
  cell_types:
  - preferred_term: lymphocyte
    term:
      id: CL:0000542
      label: lymphocyte
  evidence:
  - reference: PMID:33996698
    reference_title: "Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients characteristically present with an increased risk of infections, autoimmune cytopenias, multi-organ autoimmunity, and inflammation, which are often severe and life-threatening."
    explanation: Establishes lymphoproliferative and inflammatory disease as characteristic of this disease group.
  downstream:
  - target: EBV-Driven Lymphoproliferative Disease
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - persistent EBV infection of expanded B cells
    description: Lymphoproliferation in the presence of uncontrolled EBV creates the substrate for EBV-positive lymphoma.
- name: EBV-Driven Lymphoproliferative Disease
  biological_scale: ORGANISM
  description: >-
    The terminal event of the EBV arm: recurrent EBV-positive lymphoproliferation
    and, in the proband of the second family, EBV-positive nodular sclerosis
    classic Hodgkin lymphoma at age 10, treated with autologous stem cell
    transplantation and followed by further episodes at persistently high EBV
    loads.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:32562707
    reference_title: "DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the index case patient (patient 2) experienced an EBV -\npositive nodular sclerosis classic Hodgkin lymphoma (HL)"
    explanation: Documents EBV-driven Hodgkin lymphoma as the terminal event of this arm.
- name: Impaired Control of Epstein-Barr Virus
  biological_scale: ORGANISM
  description: >-
    The second reported family established a distinct arm not evident in the
    index report: chronic high-level EBV viraemia and EBV-driven
    lymphoproliferation, including EBV-positive nodular sclerosis classic
    Hodgkin lymphoma in the proband. This is why the second report titled the
    condition a mendelian susceptibility to EBV infection.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:32562707
    reference_title: "DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients 1 and 3 also showed abnormal detectable blood EBV\nloads (>4 log copies/mL) over 6 months"
    explanation: Documents sustained high EBV viral loads in affected siblings.
  - reference: PMID:32562707
    reference_title: "DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the index case patient (patient 2) experienced an EBV -\npositive nodular sclerosis classic Hodgkin lymphoma (HL)"
    explanation: Documents EBV-driven Hodgkin lymphoma in the proband of the second family.
  downstream:
  - target: EBV-Driven Lymphoproliferative Disease
    causal_link_type: DIRECT
    description: Failure to control EBV in B cells is what makes the lymphoproliferation EBV-positive and drives it toward lymphoma.
phenotypes:
- name: Autoimmune cytopenia
  category: Hematologic
  frequency: FREQUENT
  description: >-
    Autoimmune haemolytic anaemia and immune thrombocytopenia, which may be
    severe and refractory. In the second family the youngest sibling presented
    in the first year of life with a haemoglobin of 3.5 g/dL and a strongly
    positive Coombs test, requiring repeated transfusion.
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: PMID:33996698
    reference_title: "Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients characteristically present with an increased risk of infections, autoimmune cytopenias, multi-organ autoimmunity, and inflammation, which are often severe and life-threatening."
    explanation: Autoimmune cytopenias are a characteristic presenting feature of this disease group.
- name: Susceptibility to Epstein-Barr virus and cytomegalovirus
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Viral susceptibility in DEF6 deficiency is narrow, not general. EBV is the
    distinctive vulnerability, and CMV replication occurred in the two patients
    without a second pathogenic variant. Severe or opportunistic infections
    beyond these — bacterial sepsis and respiratory viruses — were reported only
    in the two patients who also carried a homozygous SKIV2L variant, so they are
    deliberately not curated here as DEF6 phenotypes. See the
    def6_skiv2l_confound discussion.
  phenotype_term:
    preferred_term: Susceptibility to viral infection
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: PMID:32562707
    reference_title: "DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 4 patients reported here did not have cardiac or digestive\nabnormalities and did not experience severe or opportunistic\ninfections (except EBV). In Serwas et al ,4 all of these symptoms\nwere restricted to both carriers of an additional SKIV2L variant"
    explanation: >-
      Restricts the infection phenotype to EBV in the unconfounded family and
      attributes the broader infection susceptibility to the SKIV2L carriers,
      which is why this phenotype is scoped to EBV and CMV.
  - reference: PMID:32562707
    reference_title: "DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Except for CMV in\npatient 4, there was no evidence for other viral infection"
    explanation: >-
      Carries the CMV half of this phenotype explicitly, and simultaneously
      excludes any other viral susceptibility in the unconfounded family.
- name: Persistent EBV viremia
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Chronic high-level EBV viraemia, above 4 log copies/mL sustained over
    months. Three of the four siblings in the unconfounded family carried
    detectable loads; this is the phenotype the second report named the disease
    for.
  phenotype_term:
    preferred_term: persistent Epstein-Barr virus viremia
    term:
      id: HP:0020072
      label: Persistent EBV viremia
  evidence:
  - reference: PMID:32562707
    reference_title: "DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients 1 and 3 also showed abnormal detectable blood EBV\nloads (>4 log copies/mL) over 6 months"
    explanation: Documents sustained high-level EBV viraemia in affected siblings.
- name: Lymphadenopathy
  category: Hematologic
  frequency: OCCASIONAL
  description: >-
    Lymph node enlargement, part of the lymphoproliferative arm. In the second
    family the eldest sibling developed cervical lymph node enlargement that
    regressed spontaneously, while the proband had recurrent EBV-driven
    lymphoproliferations.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:32562707
    reference_title: "DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recently developed cervical\nlymph node enlargement with spontaneous regression"
    explanation: Directly documents lymph node enlargement in the eldest affected sibling.
- name: Hepatosplenomegaly
  category: Hematologic
  frequency: OCCASIONAL
  description: >-
    Enlargement of liver and spleen, reported among the clinical features of
    DEF6-mutated patients in the index cohort.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:31308374
    reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical and immunological phenotypes in DEF6-mutated\npatients include T-cell lymphopenia, low class-switched B cells,\nhepatosplenomegaly, autoimmune hemolytic anemia"
    explanation: >-
      Listed among the clinical phenotypes of DEF6-mutated patients in the index
      report. Graded PARTIAL because that cohort includes the two SKIV2L
      carriers and the report does not resolve the finding per patient.
- name: Lymphoma
  category: Neoplastic
  frequency: OCCASIONAL
  description: >-
    EBV-positive nodular sclerosis classic Hodgkin lymphoma occurred in the
    proband of the second family at age 10. The disease group as a whole carries
    an increased risk of lymphoma, particularly non-Hodgkin lymphoma.
  phenotype_term:
    preferred_term: Lymphoma
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - reference: PMID:32562707
    reference_title: "DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the index case patient (patient 2) experienced an EBV -\npositive nodular sclerosis classic Hodgkin lymphoma (HL)"
    explanation: Documents lymphoma in a DEF6-deficient patient.
  - reference: PMID:33996698
    reference_title: "Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "these patients suffer an increased risk of developing malignancies, especially Non-Hodgkin's lymphoma"
    explanation: Establishes elevated lymphoma risk across the CTLA-4/LRBA/DEF6 group.
inheritance:
- name: Autosomal recessive
  description: >-
    Both reports describe biallelic (homozygous) DEF6 variants. In the second
    family Sanger sequencing confirmed homozygosity in all four affected
    siblings of a consanguineous kindred while both parents were heterozygous
    and unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:31308374
    reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identify biallelic mutations in three patients from two unrelated families"
    explanation: Biallelic variants in affected individuals from unrelated families indicate recessive inheritance.
genetic:
- name: DEF6
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: DEF6
    term:
      id: hgnc:2760
      label: DEF6
  notes: >-
    DEF6 encodes a guanine nucleotide exchange factor acting on the Rho GTPases
    Cdc42 and Rac1 and recruited to the immunological synapse during T-cell
    receptor signalling. Reported disease alleles are homozygous missense
    variants (p.Tyr210Asp; p.Glu331Lys) and a homozygous nonsense variant
    (p.Gln314Ter) behaving as a null.
  evidence:
  - reference: PMID:31308374
    reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity"
    explanation: Identifies DEF6 as the causative gene.
experimental_models:
- name: DEF6-knockout Jurkat T-cell line
  experimental_model_type: CELL_LINE
  description: >-
    A DEF6-knockout human T-cell line generated in the index report. It is the
    strongest causality evidence in the disease: the patient CTLA-4 trafficking
    defect is reproduced in cells whose only relevant difference is the absence
    of DEF6, which rules out the patient-specific confounders (including the
    SKIV2L variant carried by two of the three index patients) that the
    observational data cannot.
  modeled_mechanisms:
  - target: Reduced Surface CTLA-4 Availability
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The knockout line reproduces the impaired CTLA-4 surface trafficking seen
      in patient T cells.
    limitations: >-
      Jurkat is a transformed leukaemic line, not a primary regulatory T cell,
      so it models the trafficking machinery rather than Treg suppressive
      function, and it cannot speak to the organism-level autoimmunity.
    readouts:
    - name: Surface CTLA-4 availability on stimulated T cells
      target: Reduced Surface CTLA-4 Availability
      direction: DECREASED
      interpretation: >-
        Reduced functional CTLA-4 at the cell surface is the measurement that
        makes this line informative for the node.
      evidence:
      - reference: PMID:31308374
        reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "which is replicated in DEF6-knockout Jurkat cells"
        explanation: The knockout line reproduces the reduced surface CTLA-4 measured in patient T cells.
    evidence:
    - reference: PMID:31308374
      reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "which is replicated in DEF6-knockout Jurkat cells"
      explanation: States that the patient CTLA-4 trafficking phenotype is reproduced in the knockout line.
  evidence:
  - reference: PMID:31308374
    reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells."
    explanation: Establishes the knockout line as an informative model of the CTLA-4 trafficking defect.
treatments:
- name: Abatacept (CTLA-4-Ig)
  therapeutic_modality: PROTEIN_REPLACEMENT
  description: >-
    A soluble CTLA-4-Ig fusion protein that supplies extracellularly the
    B7-binding function the patient's T cells cannot deliver to their own
    surface — a direct pharmacological substitution for the trafficking defect.
    One patient in the index report achieved sustained remission on it. The
    evidence for this disease is therefore a single treated patient, and the
    supporting review evidence is extrapolated from the larger CTLA-4
    insufficiency and LRBA deficiency cohorts.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: abatacept
      term:
        id: NCIT:C28898
        label: Abatacept
  target_mechanisms:
  - target: Defective Regulatory T Cell Suppression
    treatment_effect: BYPASSES
    description: >-
      Soluble CTLA-4-Ig binds B7 ligands directly, restoring the co-stimulatory
      blockade that surface-CTLA-4-deficient Tregs cannot impose.
  evidence:
  - reference: PMID:31308374
    reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of the patients has been treated with CTLA-4-Ig and achieved sustained remission."
    explanation: The single reported treatment response in DEF6 deficiency.
  - reference: PMID:33996698
    reference_title: "Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Successful treatment options include regular administration of soluble CTLA-4-Ig fusion protein, Treg cell-sparing immune suppressants like sirolimus or mycophenolate mofetil, and hematopoietic stem cell transplantation."
    explanation: >-
      Review-level support for CTLA-4-Ig, but stated for the CTLA-4/LRBA/DEF6
      group as a whole rather than for DEF6 deficiency specifically.
- name: Hematopoietic stem cell transplantation
  therapeutic_modality: CELL_THERAPY
  description: >-
    Allogeneic HSCT is the only potentially curative option in this group of
    immune-dysregulation disorders. No DEF6-specific transplant outcome series
    exists; the recommendation is extrapolated from CTLA-4 insufficiency and
    LRBA deficiency.
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Biallelic DEF6 Loss of Function
    treatment_effect: BYPASSES
    description: >-
      Donor engraftment supplies DEF6-competent lymphocytes; it does not correct
      the patient's own DEF6 alleles, which is why this is a bypass rather than a
      restoration of the node as named.
  evidence:
  - reference: PMID:41158012
    reference_title: "CTLA4-related primary immune dysregulatory disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "hematopoietic stem cell transplantation (HSCT) remains the only curative option"
    explanation: >-
      Review states HSCT is the only curative option for the CTLA4-related
      disorders; DEF6-specific transplant evidence is absent.
- name: Immunoglobulin replacement
  therapeutic_modality: PROTEIN_REPLACEMENT
  description: >-
    Regular immunoglobulin substitution, documented in the index report's first
    patient, in whom recurrent infections requiring antibiotics persisted
    alongside it. That patient is one of the two SKIV2L carriers, so this is
    supportive rather than established practice for DEF6 deficiency
    specifically.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Impaired Class-Switched B Cell Compartment
    treatment_effect: BYPASSES
    description: >-
      Substituting immunoglobulin supplies the antibody the impaired
      class-switched compartment cannot, without addressing the CTLA-4
      trafficking lesion behind it. It is directed at the humoral deficit, not
      at the autoimmunity - replacement-dose immunoglobulin is not the
      high-dose immunomodulatory intervention.
  evidence:
  - reference: PMID:31308374
    reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regular immunoglobulin treatment is\ngiven. Recurrent infections requiring antibiotic treatment have\npersisted"
    explanation: >-
      Documents immunoglobulin substitution in the index report's first patient.
      Graded PARTIAL because that patient also carried the SKIV2L variant, so the
      indication cannot be attributed to DEF6 alone.
- name: Treg-sparing immunosuppression (sirolimus, mycophenolate mofetil)
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Immunosuppressants chosen to spare the regulatory T-cell compartment, which
    is already functionally impaired by the CTLA-4 shortage. As with abatacept
    and HSCT, the recommendation is made for the CTLA-4 / LRBA / DEF6 group as a
    whole rather than for DEF6 deficiency specifically.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
    - preferred_term: mycophenolate mofetil
      term:
        id: CHEBI:8764
        label: mycophenolate mofetil
  target_mechanisms:
  - target: Systemic Autoimmunity
    treatment_effect: INHIBITS
    description: Suppresses the effector arm of the autoimmunity while sparing the residual regulatory T-cell compartment.
  evidence:
  - reference: PMID:33996698
    reference_title: "Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Successful treatment options include regular administration of soluble CTLA-4-Ig fusion protein, Treg cell-sparing immune suppressants like sirolimus or mycophenolate mofetil, and hematopoietic stem cell transplantation."
    explanation: >-
      Review-level support for Treg-sparing immunosuppression, stated for the
      CTLA-4/LRBA/DEF6 group rather than for DEF6 deficiency alone.
- name: Second-line immunosuppression for refractory autoimmune cytopenia
  therapeutic_modality: OTHER
  description: >-
    In the youngest sibling of the unconfounded family, severe autoimmune
    haemolytic anaemia and thrombocytopenia were treated with corticosteroids,
    rituximab, azathioprine and bortezomib together with plasma exchange. The
    report describes the response as only moderate, which is the informative
    part: conventional escalation does not control the cytopenias well in this
    disease, and that is the argument for going to mechanism-directed CTLA-4-Ig
    or to transplant.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Systemic Autoimmunity
    treatment_effect: INHIBITS
    description: Broad immunosuppression and antibody removal directed at the autoimmune cytopenia rather than at its cause.
  evidence:
  - reference: PMID:32562707
    reference_title: "DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment involving\nadministration of corticosteroids, rituximab, azathioprine"
    explanation: >-
      Records the second-line regimen used for refractory autoimmune cytopenia in
      this patient. Graded PARTIAL because the same sentence reports only
      moderate efficacy.
discussions:
- discussion_id: def6_skiv2l_confound
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Biallelic DEF6 Loss of Function
  - disease#DEF6 Deficiency
  prompt: >-
    Which features of the originally reported DEF6 phenotype are attributable to
    DEF6 and which to the co-occurring SKIV2L variant?
  rationale: >-
    Two of the three patients in the index report also carried a homozygous
    predicted-pathogenic SKIV2L variant. SKIV2L deficiency causes
    trichohepatoenteric syndrome, whose features — intractable diarrhoea, liver
    disease, developmental abnormality and combined immunodeficiency — overlap
    substantially with the severe digestive and cardiac involvement described in
    those patients. The second report makes this point explicitly and describes
    a four-sibling family with no other pathogenic variant detected, in whom the
    phenotype is autoimmunity and EBV susceptibility without the
    extrahaematologic features. Until more unconfounded patients are reported,
    the digestive and cardiac manifestations should not be treated as
    established DEF6 phenotypes, and the same applies to the severe bacterial and
    respiratory infections, which the second report also localises to the SKIV2L
    carriers. The phenotypes section is scoped accordingly.
  evidence:
  - reference: PMID:32562707
    reference_title: "DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, 2\nof the 3 patients were also carrying a predicted pathogenic\nhomozygous variant in SKIV2L"
    explanation: Documents the co-occurring SKIV2L variant in the index cohort.
  - reference: PMID:31308374
    reference_title: "Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "could represent\na disease-modifying factor potentially affecting cardiac function"
    explanation: >-
      The index authors reach the same conclusion independently, treating the
      SKIV2L variant as a disease modifier for the cardiac and bowel features
      while holding that it does not explain the autoimmune presentation. Both
      reports agreeing is what makes the confound a settled caveat rather than
      one group's critique of another.
- discussion_id: def6_ebv_effector_defect
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Impaired Control of Epstein-Barr Virus
  prompt: >-
    What is the effector defect that makes DEF6-deficient patients unable to
    control EBV, and is it downstream of the CTLA-4 trafficking lesion at all?
  rationale: >-
    EBV susceptibility and EBV-driven lymphoma were the presenting features of
    the second family but were not described in the index report, where the
    CTLA-4 trafficking mechanism was worked out. Reduced surface CTLA-4 explains
    loss of tolerance, but it is not an obvious explanation for failed antiviral
    control, which usually reflects a cytotoxic T-cell or NK-cell defect. Whether
    the two arms share a mechanism or DEF6 has a separate role in cytotoxic
    lymphocyte function is unresolved, and no experiment in either report
    addresses it.
📚

References & Deep Research

Deep Research

1
Falcon ▸
DEF6 Deficiency: Disease-Characteristics Research Report
Edison Scientific Literature 14 citations 2026-08-27T16:33:11.600291

DEF6 Deficiency: Disease-Characteristics Research Report

Executive summary and evidence limits

DEF6 deficiency is an ultra-rare, autosomal-recessive inborn error of immunity (IEI) caused by biallelic loss-of-function/hypomorphic variants in DEF6. It combines immunodeficiency with severe, usually infantile immune dysregulation—particularly autoimmune enteropathy, systemic autoimmunity, lymphoproliferation, hypogammaglobulinemia, poor specific-antibody responses, and recurrent infections. The defining human evidence remains the July 2019 Nature Communications report of three patients from two unrelated families; therefore, percentages below are descriptive fractions of this tiny ascertainment cohort, not population estimates. Recent 2023–2024 literature mainly places the disorder among CTLA-4-pathway Tregopathies and has not supplied a substantially larger DEF6-specific cohort. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 9-10, sogkas2021cellularandmolecular pages 4-5)

Domain Summary Evidence type Key citations
Evidence base Ultra-rare monogenic inborn error of immunity described in a foundational 2019 report of 3 affected individuals from 2 unrelated families; later literature is mainly review/contextual, with no large dedicated cohort or trial identified. Direct human cohort + later expert review (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 1-2, serwas2019humandef6deficiency pages 15-15)
Inheritance / variants Autosomal recessive pattern supported by biallelic homozygous DEF6 missense variants in consanguineous families: family A c.991G>A p.Glu331Lys (2 siblings), family B c.628T>G p.Tyr210Asp (1 patient). Both were reported as damaging and absent in homozygous state in ExAC/gnomAD/TOPMed in the source paper. Direct human genetic evidence (serwas2019humandef6deficiency pages 3-5)
Core phenotype Early-onset systemic autoimmunity with immunodeficiency: severe enteropathy/diarrhea, bowel inflammation, hepatosplenomegaly or hepatomegaly/cholestasis, cardiomyopathy/cardiac malformations, recurrent infections, and autoimmune hematologic disease in one patient. One sibling died in infancy from cardiomyopathy-related multiorgan failure. Direct human clinical evidence (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 10-11, serwas2019humandef6deficiency pages 1-2)
Laboratory phenotype Reported abnormalities included reduced CD8+ T cells, reduced Tregs, few class-switched B cells, decreased mature NK cells, hypogammaglobulinemia with poor vaccine responses, positive autoantibodies/autoimmune markers (ANCA, cardiolipin, beta2-glycoprotein, positive direct Coombs), while neutrophil phagocytosis and oxidative burst were normal. Direct human immunology/lab evidence (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 3-5)
Mechanism DEF6 deficiency impairs CTLA-4 homeostasis in T cells by disrupting DEF6-RAB11 interaction, reducing RAB11+CTLA-4 recycling vesicles, CTLA-4 cycling, ligand uptake/transendocytosis, and functional surface CTLA-4 availability. Variants also reduce DEF6 protein abundance/stability, especially p.Tyr210Asp. Direct human cellular evidence + engineered cell validation (serwas2019humandef6deficiency pages 8-9, serwas2019humandef6deficiency pages 9-10, serwas2019humandef6deficiency pages 7-8, serwas2019humandef6deficiency pages 7-7, serwas2019humandef6deficiency pages 6-7)
Diagnosis Supported approach from available evidence: molecular sequencing confirming biallelic DEF6 variants in patients with early immune dysregulation plus functional corroboration using CTLA-4 trafficking/cycling or ligand-uptake assays in T cells when available. No disease-specific formal diagnostic criteria, screening program, or validated biomarker panel was identified. Direct human evidence + expert extrapolation (serwas2019humandef6deficiency pages 1-2, serwas2019humandef6deficiency pages 10-11, sogkas2021cellularandmolecular pages 4-5)
Treatment Directly reported care included immunoglobulin replacement, antibiotics/anti-infectives, conventional immunosuppression for autoimmune complications, and targeted CTLA-4-Ig (abatacept). One patient treated from 15 months had marked improvement and sustained remission over ~4 years. No DEF6-specific HSCT, gene therapy, RNA therapy, or trial evidence was identified. Direct human treatment evidence (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 1-2, serwas2019humandef6deficiency pages 10-11)
Prognosis Clinical course appears severe and variable: 1 of 3 known patients died in infancy; another had sustained remission of autoimmunity and stable cardiorespiratory status on abatacept; persistent infection susceptibility remained a concern despite supportive therapy. Long-term survival, penetrance, and natural-history estimates are unknown. Direct human follow-up evidence (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 10-11)
Major knowledge gaps No verified disease-specific population prevalence/incidence, no large natural-history study, no robust genotype-phenotype map, no established penetrance estimate, no DEF6-specific interventional trial, no validated prevention strategy, and no standardized diagnostic or management guideline. Mouse/model work suggests broader roles in T-cell signaling, TFH/TH17 biology, lupus-like disease, arthritis, and osteoclastogenesis, but these are not yet equivalent to proven human disease features. Explicit gap statement with model/extrapolation boundary (serwas2019humandef6deficiency pages 9-10, manni2017regulationofsystemic pages 6-7, binder2017def6restrainsosteoclastogenesis pages 6-8, binder2017def6restrainsosteoclastogenesis pages 3-4)

Table: This table provides a compact disease knowledge-base summary for DEF6 deficiency, separating direct human evidence from model-based extrapolation. It is useful for quickly identifying what is established, what is clinically actionable, and where major evidence gaps remain.

1. Disease information

Definition

DEF6 deficiency is a monogenic immune-regulatory disorder in which defective DEF6-dependent vesicular trafficking reduces functional CTLA-4 availability on activated conventional and regulatory T cells. Loss of this inhibitory checkpoint causes systemic autoimmunity, while broader T- and B-cell abnormalities confer susceptibility to infection. It is best classified as an IEI with immune dysregulation/systemic autoimmunity and, mechanistically, a secondary CTLA-4 trafficking disorder or Tregopathy. (serwas2019humandef6deficiency pages 1-2, serwas2019humandef6deficiency pages 9-10, sogkas2021cellularandmolecular pages 4-5)

Names and identifiers

  • Preferred name: DEF6 deficiency.
  • Descriptive synonym: immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis.
  • Gene/protein aliases: differentially expressed in FDCP6 homolog, SLAT (“SWAP-70-like adaptor of T cells”), and IBP (“IRF4-binding protein”). (serwas2019humandef6deficiency pages 15-15, serwas2019humandef6deficiency pages 1-2)
  • Disease-specific MONDO, Orphanet, MeSH, ICD-10, and ICD-11 identifiers were not verified in the retrieved evidence. A knowledge base should not substitute a generic immunodeficiency or autoimmunity code as if it were disease-specific.
  • The disease appears to correspond to the OMIM phenotype commonly called immunodeficiency 68 with or without autoimmunity, but its numerical OMIM identifier was not established by the retrieved primary text and should be verified directly against current OMIM before ingestion.

The primary data are individual-patient research records, pathology, immunophenotyping, sequencing, and functional experiments, not EHR-scale or registry-level aggregated data. Later sources are disease-level reviews.

Foundational citation and abstract quotation

Serwas NK et al., “Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis,” Nature Communications 10:3106, published July 2019. DOI/URL: https://doi.org/10.1038/s41467-019-10812-x. The PMID was not present in the retrieved full text and should be checked in PubMed rather than guessed. (serwas2019humandef6deficiency pages 15-15, serwas2019humandef6deficiency pages 14-15)

The abstract states: “Here, we identify biallelic mutations in three patients from two unrelated families … as the molecular cause of an inborn error of immunity with systemic autoimmunity.” It further reports that “Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability.” (serwas2019humandef6deficiency pages 1-2)

2. Etiology, risk, protection, and gene–environment interaction

Causal factor

The primary cause is germline biallelic DEF6 dysfunction. Two homozygous missense variants were reported:

  1. c.991G>A, p.Glu331Lys (E331K) in two siblings from family A, affecting the PH–DH region and reducing protein abundance and RAB11 binding.
  2. c.628T>G, p.Tyr210Asp (Y210D) in one patient from family B, causing marked protein instability; proteasome inhibition restored mutant protein in vitro. (serwas2019humandef6deficiency pages 3-5, serwas2019humandef6deficiency pages 9-10, serwas2019humandef6deficiency pages 5-6)

Both were predicted damaging and were absent in homozygous form from ExAC, gnomAD, and TOPMed in the 2019 analysis. They should be curated as disease-associated, functionally supported biallelic variants; current ClinVar assertions and ACMG classifications require direct database verification. (serwas2019humandef6deficiency pages 3-5)

Risk factors

  • Genetic: two pathogenic/hypomorphic alleles; parental consanguinity and an affected sibling are major family-level risk indicators. Family A was Pakistani and consanguineous; family B had consanguineous Iraqi parents. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 1-2)
  • Environmental/lifestyle: no toxins, diet, smoking, alcohol, occupation, radiation, sex-specific exposure, or lifestyle factor has been shown to cause DEF6 deficiency.
  • Infection as trigger: infection is not the primary cause, but immune challenges may reveal disease. In P3, autoimmune hemolytic anemia appeared during CMV infection; this is compatible with infection-triggered expression of autoimmunity but does not establish a general gene–environment interaction. (serwas2019humandef6deficiency pages 2-3)
  • Modifiers: no validated modifier genes, protective alleles, environmental protective factors, or epigenetic modifiers have been reported.

3. Phenotypes

Frequencies are calculated from the three published patients only and are therefore highly unstable.

Core clinical and laboratory features

  • Infantile onset: all three had clinically important disease during infancy (3/3). P1 developed watery diarrhea in the first month; P2 had neonatal/premature multisystem disease; P3 presented at seven months. Suggested HPO: HP:0003593 Infantile onset. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 10-11)
  • Enteropathy/diarrhea: severe watery diarrhea, bowel inflammation, villous atrophy, T-cell/eosinophilic infiltration, rectal/perianal lesions, or necrotizing enterocolitis-like intestinal disease occurred in both family-A siblings (2/3). Suggested HPO: Chronic diarrhea, Enteropathy, Villous atrophy, Abnormality of the gastrointestinal tract. Course was severe and chronic before targeted therapy. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 10-11, serwas2019humandef6deficiency pages 1-2)
  • Recurrent infections: reported across the cohort, involving bacterial, viral, and fungal organisms. Documented organisms included Streptococcus pneumoniae, Staphylococcus aureus, Enterobacter aerogenes, Enterococcus faecalis, rhinovirus, influenza B, RSV, rotavirus, CMV, and Malassezia furfur. Suggested HPO: HP:0002719 Recurrent infections, Recurrent respiratory infections, Viral infection, Fungal infection. (serwas2019humandef6deficiency pages 3-5)
  • Liver/lymphoid-organ disease: hepatomegaly or hepatosplenomegaly occurred in the family-A patients; P2 developed cholestasis and liver failure. Suggested HPO: HP:0002240 Hepatomegaly, HP:0001744 Splenomegaly, HP:0001396 Cholestasis, Liver failure. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 10-11)
  • Cardiac disease: the siblings had cardiomyopathy and/or congenital structural heart disease; P2 had atrioventricular septal defect, progressive heart failure and pacemaker requirement, while P1 had biventricular hypertrophy and atrial septal defect. Suggested HPO: HP:0001638 Cardiomyopathy, HP:0001631 Atrial septal defect, HP:0006695 Atrioventricular septal defect, HP:0001635 Congestive heart failure. Whether congenital heart anomalies are intrinsic DEF6 manifestations remains uncertain because only one family was affected. (serwas2019humandef6deficiency pages 10-11)
  • Autoimmune cytopenia: P3 developed autoimmune hemolytic anemia during CMV infection (1/3); direct Coombs positivity was also recorded. Suggested HPO: HP:0001890 Autoimmune hemolytic anemia, Positive direct antiglobulin test. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 3-5)
  • Autoantibodies: ANCA, anticardiolipin, anti-β2-glycoprotein and smooth-muscle antibodies were reported. Suggested HPO: HP:0002960 Autoimmunity, Abnormal circulating autoantibody concentration. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 3-5)
  • Immunologic abnormalities: T-cell/CD8 lymphopenia, reduced CD25-high/CD127-low/FOXP3-positive Tregs, low class-switched memory B cells, decreased mature NK cells, hypogammaglobulinemia and poor tetanus/pneumococcal antibody responses were found variably. P1 had IgG 1.60 g/L, IgA 0.009 g/L and IgM 0.17 g/L at one assessment; neutrophil phagocytosis and oxidative burst were normal. Suggested HPO: HP:0005403 T-cell lymphopenia, HP:0004313 Decreased circulating antibody level, Hypogammaglobulinemia, Impaired specific antibody response, Decreased switched memory B-cell count, and Decreased regulatory T-cell count. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 3-5)

Severity, progression, and quality of life

Severity ranged from life-threatening infantile multiorgan disease to treatable chronic immune dysregulation. Enteropathy impaired nutrition and required intensive care/parenteral nutrition in P2; recurrent infection and cardiopulmonary disease increased care burden. No EQ-5D, SF-36, PROMIS, developmental, educational, or formal disability measurements have been published. One patient died at 10.5 months; P1 achieved sustained control of autoimmunity with abatacept. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 10-11)

4. Genetic and molecular information

  • Causal gene: DEF6; HGNC/NCBI Gene/Ensembl/OMIM gene numbers should be imported from their current authoritative records rather than inferred from this literature set.
  • Inheritance: autosomal recessive; variants are constitutional/germline, not somatic. (serwas2019humandef6deficiency pages 1-2, serwas2019humandef6deficiency pages 3-5)
  • Variant classes: both known disease alleles are missense variants with partial or severe loss of protein/function. E331K is defective in RAB11 interaction and functional rescue; Y210D is strongly destabilized. Thus, the most defensible functional annotation is loss of function/hypomorphic loss of function, not gain of function or dominant negative. (serwas2019humandef6deficiency pages 5-6, serwas2019humandef6deficiency pages 8-9, serwas2019humandef6deficiency pages 9-10)
  • Population frequency: no homozygotes in the population resources queried in 2019; exact allele frequencies were not available in the retrieved excerpts. (serwas2019humandef6deficiency pages 3-5)
  • Protein architecture: DEF6 contains an N-terminal EF-hand, ITAM-like sequence, phosphoinositide-binding PH domain and C-terminal DH-like GEF region. Resting DEF6 is autoinhibited; TCR engagement and LCK-mediated phosphorylation open the molecule and recruit it to the immunological synapse. (binder2017def6restrainsosteoclastogenesis pages 3-4, binder2017def6restrainsosteoclastogenesis pages 11-12, manni2017regulationofsystemic pages 12-14)
  • Modifier genes, epigenetics, and chromosomal abnormalities: none established. There is no evidence that aneuploidy, translocation, inversion, methylation disorder, repeat expansion, or mitochondrial mutation causes this phenotype.

5. Environmental and infectious information

There is no evidence for a primary environmental, toxic, dietary, occupational, radiation, or lifestyle etiology. Infectious agents are complications or possible immune triggers, not inherited-cause substitutes. CMV coincided with hemolytic anemia in P3, while respiratory, enteric, bacterial and fungal infections reflected immunodeficiency. No zoonotic or transmissible form exists. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 3-5)

6. Mechanism and pathophysiology

Principal human causal chain

Biallelic DEF6 variant → reduced/unstable DEF6 or impaired PH–DH function → defective binding/GEF activity toward RAB11 → loss of RAB11-positive CTLA-4 recycling vesicles → impaired CTLA-4 cycling to the T-cell surface → reduced CD80/CD86 capture and transendocytosis → inadequate inhibition of antigen-presenting-cell/T-cell costimulation → systemic autoimmunity and lymphoproliferation. Parallel defects in T-cell signaling, lymphocyte composition and antibody responses contribute to infection susceptibility. (serwas2019humandef6deficiency pages 8-9, serwas2019humandef6deficiency pages 9-10, serwas2019humandef6deficiency pages 7-8, serwas2019humandef6deficiency pages 7-7)

The evidence is unusually strong for an ultra-rare disease: patient CD4 T cells and memory Tregs had impaired CTLA-4 cycling; CRISPR DEF6-knockout Jurkat cells phenocopied the defect; wild-type DEF6 rescued it, whereas E331K did not; RAB11 abundance itself was normal; and co-immunoprecipitation established DEF6–RAB11 interaction. (serwas2019humandef6deficiency pages 8-9, serwas2019humandef6deficiency pages 7-8, serwas2019humandef6deficiency pages 6-7, serwas2019humandef6deficiency pages 9-9)

Suggested annotations:

  • GO biological processes: T-cell receptor signaling, regulation of immune response, vesicle-mediated transport, recycling endosome organization, regulation of T-cell activation, small-GTPase-mediated signal transduction, actin cytoskeleton organization, and calcium-mediated signaling.
  • GO cellular components: immunological synapse, recycling endosome, cytoplasmic vesicle, plasma membrane, cytosol, and nucleus.
  • Cell Ontology: CL:0000084 T cell, CL:0000815 regulatory T cell, CL:0000624 CD4-positive alpha-beta T cell, CL:0000785 mature B cell, CL:0000623 natural killer cell, CL:0000235 macrophage, and CL:0000092 osteoclast.

Additional DEF6 biology—model or contextual evidence

In T cells, DEF6 activates RAC and CDC42, regulates actin dynamics, synapse formation and Ca²⁺/NFAT signaling, sequesters IRF4, limits ROCK2-dependent IRF4 phosphorylation, and restrains TH17/IL-17/IL-21 and TFH programs. It also inhibits assembly of a p62–TRAF6–Raptor complex, thereby regulating mTORC1-dependent translation, including BCL6. These pathways plausibly modify the human phenotype but the RAB11–CTLA-4 defect is the mechanism directly demonstrated in patients. (manni2017regulationofsystemic pages 3-4, manni2017regulationofsystemic pages 12-14)

In myeloid/osteoclast models, DEF6 promotes an autocrine IFN-β brake on the c-FOS–NFATC1–BLIMP1 osteoclastogenic axis. Def6-null precursors are hypersensitive to RANKL and can undergo TNF-driven osteoclastogenesis; mice develop reduced trabecular bone and enhanced inflammatory erosion. These are credible downstream biological roles but osteoporosis or inflammatory arthritis has not yet been established as a recurrent human DEF6-deficiency phenotype. (binder2017def6restrainsosteoclastogenesis pages 9-11, binder2017def6restrainsosteoclastogenesis pages 6-8)

No disease-specific single-cell, spatial-transcriptomic, metabolomic, lipidomic, patient proteomic, organoid, iPSC, or multi-omics signature has been validated. The 2019 work used primary immune cells, conventional immunophenotyping, microscopy, co-immunoprecipitation and engineered cell models rather than clinical multi-omics.

7. Anatomical structures affected

Directly observed sites include:

  • Immune/lymphoid system: circulating T, B and NK cells; spleen and lymphoid compartments. Suggested UBERON: blood, spleen, lymph node, thymus.
  • Gastrointestinal tract: stomach, duodenum, colon, rectum/perianal region; mucosa and villi were affected. Suggested UBERON: stomach, duodenum, colon, rectum, intestinal mucosa, intestinal villus. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 1-2)
  • Liver: hepatomegaly, cholestasis and liver failure in severe disease. Suggested UBERON: liver, intrahepatic biliary system. (serwas2019humandef6deficiency pages 10-11)
  • Heart: myocardium and septal structures in family A. Suggested UBERON: heart, myocardium, atrial septum, ventricular septum. (serwas2019humandef6deficiency pages 10-11)
  • Bone in models: trabecular bone and osteoclast surfaces; human relevance remains unproven. (binder2017def6restrainsosteoclastogenesis pages 6-8)

At the subcellular level, the critical sites are the recycling endosome, CTLA-4-positive vesicle, immunological synapse, plasma membrane, cytosol and nucleus. No consistent lateralization is applicable.

8. Temporal development and natural history

Typical recognized onset is congenital/infantile, often chronic and multisystemic. The course can be progressive, episodic with infections, or treatment-responsive. P1 began with diarrhea during the first month; P3 presented at seven months; P2 had severe neonatal/infantile disease and died at 10.5 months. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 10-11)

No validated stages exist. A pragmatic clinical sequence is: early infection/enteropathy or autoimmune cytopenia → evolving lymphoproliferation, antibody deficiency and systemic autoimmunity → organ complications. Remission may be treatment-induced: P1's bowel inflammation improved within approximately one month of abatacept, and no overt autoimmune recurrence was reported over about four years. No spontaneous-remission rate or critical intervention window has been quantified, although the observed infantile severity supports early genomic diagnosis and immune-directed treatment. (serwas2019humandef6deficiency pages 2-3)

9. Inheritance and population

  • Pattern: autosomal recessive.
  • Penetrance: apparently high among the three biallelic affected individuals, but numerically unknowable; age-dependent and organ-specific penetrance cannot be estimated.
  • Expressivity: clearly variable, including lethal infantile cardiomyopathy/multiorgan failure, predominant enteropathy, and CMV-associated autoimmune hemolysis.
  • Anticipation, germline mosaicism and founder effect: not reported.
  • Consanguinity: present in both discovery families and important for case ascertainment, but not biologically required for autosomal-recessive disease. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 1-2)
  • Prevalence/incidence/carrier frequency: unknown; no cases-per-100,000 estimate or registry-based denominator exists.
  • Demographics: two girls were siblings in a Pakistani family; P3 came from an Iraqi family. The dataset is too small to infer ethnicity, geography, sex ratio or age distribution. No sex-limited inheritance exists.

10. Diagnostics

Clinical recognition

Consider DEF6 deficiency in an infant or child with a CTLA-4/LRBA-like syndrome: autoimmune enteropathy, autoimmune cytopenia, hepatosplenomegaly/lymphoproliferation, hypogammaglobulinemia or impaired vaccine responses, and recurrent infections—especially with consanguinity or similarly affected siblings. DEF6-mutated patients may lack some T-cell activation/exhaustion features described in CTLA4 or LRBA disease, so phenotype alone is insufficient. (serwas2019humandef6deficiency pages 9-10, sogkas2021cellularandmolecular pages 4-5)

Recommended work-up

  1. CBC with differential; lymphocyte subsets and naïve/memory phenotyping.
  2. Quantitative IgG/IgA/IgM and vaccine-specific antibodies.
  3. Treg enumeration using an age-appropriate CD4/CD25-high/CD127-low/FOXP3 panel.
  4. Autoimmune testing guided by presentation: direct antiglobulin test, hemolysis profile, ANCA, antiphospholipid and organ-specific antibodies.
  5. Microbiological testing, including CMV/EBV where clinically indicated.
  6. Fecal calprotectin, endoscopy and intestinal biopsy for severe diarrhea; biopsy may show villous atrophy and lymphocytic/eosinophilic infiltration.
  7. Cardiac echocardiography/ECG where symptoms or family history warrant it; liver chemistry and imaging for hepatobiliary disease. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 3-5, serwas2019humandef6deficiency pages 10-11)

Genetic diagnosis

Use an IEI/immune-dysregulation panel containing DEF6, CTLA4, LRBA and other Tregopathy/autoimmune-lymphoproliferation genes, or trio WES/WGS when the phenotype is broad. Confirm candidate variants by an orthogonal method and test segregation. Single-gene sequencing is efficient when a familial DEF6 variant is known. Copy-number analysis should accompany sequencing where technically possible. CMA, karyotype, FISH, mitochondrial and repeat-expansion testing are not first-line unless another diagnosis is suspected.

Functional confirmation may include DEF6 protein abundance, stimulated CTLA-4 expression/cycling, CD80/CD86 uptake or transendocytosis, and RAB11–CTLA-4 colocalization in specialized laboratories. These are research-supported assays, not standardized diagnostic criteria. (serwas2019humandef6deficiency pages 8-9, serwas2019humandef6deficiency pages 7-8, serwas2019humandef6deficiency pages 7-7, serwas2019humandef6deficiency pages 1-2)

Differential diagnosis

Major differentials include CTLA-4 haploinsufficiency, LRBA deficiency, FOXP3/IPEX, activated PI3Kδ syndrome, STAT3 gain-of-function disease, autoimmune lymphoproliferative syndrome, common variable immunodeficiency, NBEAL2 deficiency with immune dysregulation, and monogenic inflammatory bowel disease. The strongest mechanistic mimics are CTLA4 and LRBA disorders because all reduce functional CTLA-4 checkpoint activity. (serwas2019humandef6deficiency pages 9-10, sogkas2021cellularandmolecular pages 4-5)

No population or newborn screening program exists. Cascade testing is appropriate after molecular diagnosis.

11. Outcome and prognosis

One of the three discovery patients died at 10.5 months from cardiomyopathy-associated multiorgan failure, giving a crude discovery-cohort mortality of 1/3, which must not be interpreted as a population mortality rate. P1 remained without overt recurrent autoimmunity and had stable cardiorespiratory function approximately four years after starting abatacept. Persistent infection susceptibility can continue despite immunoglobulin replacement and immune control. (serwas2019humandef6deficiency pages 2-3)

No five- or ten-year survival rate, median life expectancy, validated prognostic score, disability scale, or prognostic biomarker exists. Plausible adverse indicators include neonatal onset, severe enteropathy, cardiomyopathy, liver failure, recurrent sepsis, profound lymphopenia and uncontrolled autoimmunity, but none has been validated statistically.

12. Treatment and current implementation

Treatment is individualized in an expert pediatric immunology/IEI center.

  • Abatacept (CTLA-4-Ig): the principal mechanism-directed therapy. P1 began four-weekly abatacept at 15 months. Bowel inflammation improved within about one month, villous atrophy and lymphocytic infiltration resolved, perianal lesions reversed, and remission persisted for approximately four years. This is compelling single-patient precision-medicine evidence, not a response-rate trial. Suggested NCIt term: Abatacept / CTLA-4 immunoglobulin. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 1-2)
  • Immunoglobulin replacement: used for low immunoglobulins and poor vaccine titers; all reported patients received regular immunoglobulin treatment. Suggested NCIt: Intravenous Immunoglobulin Therapy or Immunoglobulin Replacement Therapy. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 10-11)
  • Anti-infective therapy: organism-directed antibiotics and antivirals; P3 received ganciclovir/valganciclovir for CMV. Suggested NCIt: Antibiotic Therapy, Antiviral Therapy, Ganciclovir, Valganciclovir. (serwas2019humandef6deficiency pages 2-3)
  • Conventional immunosuppression: corticosteroids and azathioprine were used for autoimmune hemolytic anemia. Suggested NCIt: Corticosteroid Therapy, Azathioprine. (serwas2019humandef6deficiency pages 2-3)
  • Organ-supportive care: nutritional therapy, management of heart failure and structural cardiac disease, and liver/critical-care support according to phenotype. P1 received enalapril, atenolol, spironolactone and furosemide for cardiac disease. (serwas2019humandef6deficiency pages 10-11)

No DEF6-specific randomized trial, approved gene therapy, CRISPR therapy, RNA therapy, CAR-T approach, or published DEF6-specific hematopoietic stem-cell transplantation outcome was identified. HSCT may be discussed by analogy with severe immune-dysregulation IEIs, but efficacy and risk in DEF6 deficiency are unknown. Abatacept can itself contribute to infection risk, requiring surveillance. (serwas2019humandef6deficiency pages 9-10)

13. Prevention

The genetic defect cannot presently be prevented by lifestyle modification.

  • Primary prevention/family planning: genetic counseling, parental carrier testing, reproductive options including preimplantation genetic testing and prenatal diagnosis once familial variants are known.
  • Secondary prevention: cascade testing of siblings and relatives; prompt evaluation of infants at 25% Mendelian recurrence risk; early immune, gastrointestinal, hepatic and cardiac assessment.
  • Tertiary prevention: immunoglobulin replacement where indicated, rapid treatment of infections, vaccination planning under immunology guidance, monitoring for CMV/other opportunistic infection when immunosuppressed, surveillance for enteropathy, cytopenias, liver disease and cardiac dysfunction, and early control of autoimmunity.

No DEF6-specific vaccine, antimicrobial-prophylaxis regimen, public-health program, newborn screen or evidence-based behavioral intervention exists. Live-vaccine decisions must be individualized to immune competence rather than inferred solely from genotype.

14. Other species and natural disease

The human disorder is not infectious or zoonotic. No naturally occurring veterinary DEF6-deficiency syndrome or breed association was identified. The principal comparative species is mouse (Mus musculus, NCBI Taxon 10090), which has the ortholog Def6. Ortholog-specific NCBI Gene and VBO identifiers require direct database retrieval.

Evolutionary conservation is supported by shared roles in lymphocyte signaling and autoimmunity, but mouse manifestations are highly background-dependent. Consequently, mouse lupus, arthritis and bone phenotypes should be annotated as comparative-model evidence—not natural human manifestations. (biswas2010irf4andits pages 14-15, binder2017def6restrainsosteoclastogenesis pages 3-4)

15. Model organisms and experimental systems

Mouse models

  • Def6-null, mixed 129/B6 background: approximately 60% of females developed lupus-like disease by five months, including lymphadenopathy, splenomegaly, hypergammaglobulinemia, anti-dsDNA antibodies and glomerulonephritis. (biswas2010irf4andits pages 14-15)
  • Def6-null × DO11.10 TCR-transgenic BALB/c: RA-like disease began around two months, with symmetric joint swelling, synovitis, pannus, cartilage/subchondral bone destruction, rheumatoid factor and anti-CCP antibodies. (biswas2010irf4andits pages 14-15, biswas2010irf4andits pages 15-16)
  • Def6/Swap70 double knockout: female-biased systemic autoimmunity, TFH/TH17 expansion, aged/atypical CD11c-positive T-bet-positive B-cell accumulation, anti-DNA/nuclear antibodies and immune-complex glomerulonephritis; IL-21 signaling is important. (manni2017regulationofsystemic pages 6-7, manni2017regulationofsystemic pages 7-9)
  • C57BL/6 Def6-null: may lack spontaneous autoantibodies/systemic disease, highlighting strain effects. Independently, these mice show excessive RANKL/TNF-driven osteoclastogenesis, osteopenia and inflammatory bone erosion. (binder2017def6restrainsosteoclastogenesis pages 6-8, binder2017def6restrainsosteoclastogenesis pages 3-4)

Cellular models

Primary patient PBMCs/CD4 T cells, feeder-expanded T cells, CRISPR DEF6-knockout Jurkat cells, reconstitution with wild-type or E331K DEF6, and HEK293T co-immunoprecipitation systems established the RAB11–CTLA-4 trafficking mechanism. Wild-type—but not mutant—DEF6 rescued trafficking, satisfying a strong functional-causality criterion. (serwas2019humandef6deficiency pages 8-9, serwas2019humandef6deficiency pages 9-10, serwas2019humandef6deficiency pages 7-8)

Model limitations

Mouse disease depends strongly on strain, sex, TCR transgene and concurrent Swap70 loss. Mice prominently model lupus, arthritis and bone loss, whereas the known human syndrome emphasizes infantile enteropathy, infections, antibody deficiency and CTLA-4 trafficking. Jurkat and overexpression systems clarify molecular interactions but cannot reproduce tissue-level disease, development, infection susceptibility or treatment toxicity.

Current assessment and priority research needs

The most authoritative interpretation is that DEF6 deficiency is a RAB11-dependent CTLA-4 recycling disorder with broader TCR-signaling effects. The abatacept response is a notable real-world example of mechanism-guided therapy, but it rests on one treated patient. Priorities are international case aggregation, standardized phenotyping and CTLA-4 functional assays, contemporary ClinVar/gnomAD curation, longitudinal infection and malignancy surveillance, formal HSCT evaluation, and genotype–phenotype studies. Larger cohorts are explicitly required to define the full clinical spectrum. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 9-10)

Evidence-source hierarchy

  • Direct human clinical/genetic: Serwas et al., July 2019, DOI https://doi.org/10.1038/s41467-019-10812-x. (serwas2019humandef6deficiency pages 2-3, serwas2019humandef6deficiency pages 1-2)
  • Current expert synthesis: Sogkas et al., published April 2021, DOI https://doi.org/10.1038/s41423-020-00626-z; 2024 Tregopathy reviews support current placement but do not materially enlarge the DEF6 cohort. (sogkas2021cellularandmolecular pages 4-5)
  • Mechanistic/model literature: Binder et al., May 2017, DOI https://doi.org/10.4049/jimmunol.1601716; Manni et al., November 2017, DOI https://doi.org/10.1016/j.cellimm.2017.05.010. (binder2017def6restrainsosteoclastogenesis pages 3-4, manni2017regulationofsystemic pages 6-7)

References

  1. (serwas2019humandef6deficiency pages 2-3): Nina K. Serwas, Birgit Hoeger, Rico C. Ardy, Sigrun V. Stulz, Zhenhua Sui, Nima Memaran, Marie Meeths, Ana Krolo, Özlem Yüce Petronczki, Laurène Pfajfer, Tie Z. Hou, Neil Halliday, Elisangela Santos-Valente, Artem Kalinichenko, Alan Kennedy, Emily M. Mace, Malini Mukherjee, Bianca Tesi, Anna Schrempf, Winfried F. Pickl, Joanna I. Loizou, Renate Kain, Bettina Bidmon-Fliegenschnee, Jean-Nicolas Schickel, Salomé Glauzy, Jakob Huemer, Wojciech Garncarz, Elisabeth Salzer, Iro Pierides, Ivan Bilic, Jens Thiel, Peter Priftakis, Pinaki P. Banerjee, Elisabeth Förster-Waldl, David Medgyesi, Wolf-Dietrich Huber, Jordan S. Orange, Eric Meffre, David M. Sansom, Yenan T. Bryceson, Amnon Altman, and Kaan Boztug. Human def6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant ctla-4 homeostasis. Nature Communications, Jul 2019. URL: https://doi.org/10.1038/s41467-019-10812-x, doi:10.1038/s41467-019-10812-x. This article has 94 citations and is from a highest quality peer-reviewed journal.

  2. (serwas2019humandef6deficiency pages 9-10): Nina K. Serwas, Birgit Hoeger, Rico C. Ardy, Sigrun V. Stulz, Zhenhua Sui, Nima Memaran, Marie Meeths, Ana Krolo, Özlem Yüce Petronczki, Laurène Pfajfer, Tie Z. Hou, Neil Halliday, Elisangela Santos-Valente, Artem Kalinichenko, Alan Kennedy, Emily M. Mace, Malini Mukherjee, Bianca Tesi, Anna Schrempf, Winfried F. Pickl, Joanna I. Loizou, Renate Kain, Bettina Bidmon-Fliegenschnee, Jean-Nicolas Schickel, Salomé Glauzy, Jakob Huemer, Wojciech Garncarz, Elisabeth Salzer, Iro Pierides, Ivan Bilic, Jens Thiel, Peter Priftakis, Pinaki P. Banerjee, Elisabeth Förster-Waldl, David Medgyesi, Wolf-Dietrich Huber, Jordan S. Orange, Eric Meffre, David M. Sansom, Yenan T. Bryceson, Amnon Altman, and Kaan Boztug. Human def6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant ctla-4 homeostasis. Nature Communications, Jul 2019. URL: https://doi.org/10.1038/s41467-019-10812-x, doi:10.1038/s41467-019-10812-x. This article has 94 citations and is from a highest quality peer-reviewed journal.

  3. (sogkas2021cellularandmolecular pages 4-5): Georgios Sogkas, Faranaz Atschekzei, Ignatius Ryan Adriawan, Natalia Dubrowinskaja, Torsten Witte, and Reinhold Ernst Schmidt. Cellular and molecular mechanisms breaking immune tolerance in inborn errors of immunity. Cellular and Molecular Immunology, 18:1122-1140, Apr 2021. URL: https://doi.org/10.1038/s41423-020-00626-z, doi:10.1038/s41423-020-00626-z. This article has 103 citations and is from a peer-reviewed journal.

  4. (serwas2019humandef6deficiency pages 1-2): Nina K. Serwas, Birgit Hoeger, Rico C. Ardy, Sigrun V. Stulz, Zhenhua Sui, Nima Memaran, Marie Meeths, Ana Krolo, Özlem Yüce Petronczki, Laurène Pfajfer, Tie Z. Hou, Neil Halliday, Elisangela Santos-Valente, Artem Kalinichenko, Alan Kennedy, Emily M. Mace, Malini Mukherjee, Bianca Tesi, Anna Schrempf, Winfried F. Pickl, Joanna I. Loizou, Renate Kain, Bettina Bidmon-Fliegenschnee, Jean-Nicolas Schickel, Salomé Glauzy, Jakob Huemer, Wojciech Garncarz, Elisabeth Salzer, Iro Pierides, Ivan Bilic, Jens Thiel, Peter Priftakis, Pinaki P. Banerjee, Elisabeth Förster-Waldl, David Medgyesi, Wolf-Dietrich Huber, Jordan S. Orange, Eric Meffre, David M. Sansom, Yenan T. Bryceson, Amnon Altman, and Kaan Boztug. Human def6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant ctla-4 homeostasis. Nature Communications, Jul 2019. URL: https://doi.org/10.1038/s41467-019-10812-x, doi:10.1038/s41467-019-10812-x. This article has 94 citations and is from a highest quality peer-reviewed journal.

  5. (serwas2019humandef6deficiency pages 15-15): Nina K. Serwas, Birgit Hoeger, Rico C. Ardy, Sigrun V. Stulz, Zhenhua Sui, Nima Memaran, Marie Meeths, Ana Krolo, Özlem Yüce Petronczki, Laurène Pfajfer, Tie Z. Hou, Neil Halliday, Elisangela Santos-Valente, Artem Kalinichenko, Alan Kennedy, Emily M. Mace, Malini Mukherjee, Bianca Tesi, Anna Schrempf, Winfried F. Pickl, Joanna I. Loizou, Renate Kain, Bettina Bidmon-Fliegenschnee, Jean-Nicolas Schickel, Salomé Glauzy, Jakob Huemer, Wojciech Garncarz, Elisabeth Salzer, Iro Pierides, Ivan Bilic, Jens Thiel, Peter Priftakis, Pinaki P. Banerjee, Elisabeth Förster-Waldl, David Medgyesi, Wolf-Dietrich Huber, Jordan S. Orange, Eric Meffre, David M. Sansom, Yenan T. Bryceson, Amnon Altman, and Kaan Boztug. Human def6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant ctla-4 homeostasis. Nature Communications, Jul 2019. URL: https://doi.org/10.1038/s41467-019-10812-x, doi:10.1038/s41467-019-10812-x. This article has 94 citations and is from a highest quality peer-reviewed journal.

  6. (serwas2019humandef6deficiency pages 3-5): Nina K. Serwas, Birgit Hoeger, Rico C. Ardy, Sigrun V. Stulz, Zhenhua Sui, Nima Memaran, Marie Meeths, Ana Krolo, Özlem Yüce Petronczki, Laurène Pfajfer, Tie Z. Hou, Neil Halliday, Elisangela Santos-Valente, Artem Kalinichenko, Alan Kennedy, Emily M. Mace, Malini Mukherjee, Bianca Tesi, Anna Schrempf, Winfried F. Pickl, Joanna I. Loizou, Renate Kain, Bettina Bidmon-Fliegenschnee, Jean-Nicolas Schickel, Salomé Glauzy, Jakob Huemer, Wojciech Garncarz, Elisabeth Salzer, Iro Pierides, Ivan Bilic, Jens Thiel, Peter Priftakis, Pinaki P. Banerjee, Elisabeth Förster-Waldl, David Medgyesi, Wolf-Dietrich Huber, Jordan S. Orange, Eric Meffre, David M. Sansom, Yenan T. Bryceson, Amnon Altman, and Kaan Boztug. Human def6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant ctla-4 homeostasis. Nature Communications, Jul 2019. URL: https://doi.org/10.1038/s41467-019-10812-x, doi:10.1038/s41467-019-10812-x. This article has 94 citations and is from a highest quality peer-reviewed journal.

  7. (serwas2019humandef6deficiency pages 10-11): Nina K. Serwas, Birgit Hoeger, Rico C. Ardy, Sigrun V. Stulz, Zhenhua Sui, Nima Memaran, Marie Meeths, Ana Krolo, Özlem Yüce Petronczki, Laurène Pfajfer, Tie Z. Hou, Neil Halliday, Elisangela Santos-Valente, Artem Kalinichenko, Alan Kennedy, Emily M. Mace, Malini Mukherjee, Bianca Tesi, Anna Schrempf, Winfried F. Pickl, Joanna I. Loizou, Renate Kain, Bettina Bidmon-Fliegenschnee, Jean-Nicolas Schickel, Salomé Glauzy, Jakob Huemer, Wojciech Garncarz, Elisabeth Salzer, Iro Pierides, Ivan Bilic, Jens Thiel, Peter Priftakis, Pinaki P. Banerjee, Elisabeth Förster-Waldl, David Medgyesi, Wolf-Dietrich Huber, Jordan S. Orange, Eric Meffre, David M. Sansom, Yenan T. Bryceson, Amnon Altman, and Kaan Boztug. Human def6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant ctla-4 homeostasis. Nature Communications, Jul 2019. URL: https://doi.org/10.1038/s41467-019-10812-x, doi:10.1038/s41467-019-10812-x. This article has 94 citations and is from a highest quality peer-reviewed journal.

  8. (serwas2019humandef6deficiency pages 8-9): Nina K. Serwas, Birgit Hoeger, Rico C. Ardy, Sigrun V. Stulz, Zhenhua Sui, Nima Memaran, Marie Meeths, Ana Krolo, Özlem Yüce Petronczki, Laurène Pfajfer, Tie Z. Hou, Neil Halliday, Elisangela Santos-Valente, Artem Kalinichenko, Alan Kennedy, Emily M. Mace, Malini Mukherjee, Bianca Tesi, Anna Schrempf, Winfried F. Pickl, Joanna I. Loizou, Renate Kain, Bettina Bidmon-Fliegenschnee, Jean-Nicolas Schickel, Salomé Glauzy, Jakob Huemer, Wojciech Garncarz, Elisabeth Salzer, Iro Pierides, Ivan Bilic, Jens Thiel, Peter Priftakis, Pinaki P. Banerjee, Elisabeth Förster-Waldl, David Medgyesi, Wolf-Dietrich Huber, Jordan S. Orange, Eric Meffre, David M. Sansom, Yenan T. Bryceson, Amnon Altman, and Kaan Boztug. Human def6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant ctla-4 homeostasis. Nature Communications, Jul 2019. URL: https://doi.org/10.1038/s41467-019-10812-x, doi:10.1038/s41467-019-10812-x. This article has 94 citations and is from a highest quality peer-reviewed journal.

  9. (serwas2019humandef6deficiency pages 7-8): Nina K. Serwas, Birgit Hoeger, Rico C. Ardy, Sigrun V. Stulz, Zhenhua Sui, Nima Memaran, Marie Meeths, Ana Krolo, Özlem Yüce Petronczki, Laurène Pfajfer, Tie Z. Hou, Neil Halliday, Elisangela Santos-Valente, Artem Kalinichenko, Alan Kennedy, Emily M. Mace, Malini Mukherjee, Bianca Tesi, Anna Schrempf, Winfried F. Pickl, Joanna I. Loizou, Renate Kain, Bettina Bidmon-Fliegenschnee, Jean-Nicolas Schickel, Salomé Glauzy, Jakob Huemer, Wojciech Garncarz, Elisabeth Salzer, Iro Pierides, Ivan Bilic, Jens Thiel, Peter Priftakis, Pinaki P. Banerjee, Elisabeth Förster-Waldl, David Medgyesi, Wolf-Dietrich Huber, Jordan S. Orange, Eric Meffre, David M. Sansom, Yenan T. Bryceson, Amnon Altman, and Kaan Boztug. Human def6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant ctla-4 homeostasis. Nature Communications, Jul 2019. URL: https://doi.org/10.1038/s41467-019-10812-x, doi:10.1038/s41467-019-10812-x. This article has 94 citations and is from a highest quality peer-reviewed journal.

  10. (serwas2019humandef6deficiency pages 7-7): Nina K. Serwas, Birgit Hoeger, Rico C. Ardy, Sigrun V. Stulz, Zhenhua Sui, Nima Memaran, Marie Meeths, Ana Krolo, Özlem Yüce Petronczki, Laurène Pfajfer, Tie Z. Hou, Neil Halliday, Elisangela Santos-Valente, Artem Kalinichenko, Alan Kennedy, Emily M. Mace, Malini Mukherjee, Bianca Tesi, Anna Schrempf, Winfried F. Pickl, Joanna I. Loizou, Renate Kain, Bettina Bidmon-Fliegenschnee, Jean-Nicolas Schickel, Salomé Glauzy, Jakob Huemer, Wojciech Garncarz, Elisabeth Salzer, Iro Pierides, Ivan Bilic, Jens Thiel, Peter Priftakis, Pinaki P. Banerjee, Elisabeth Förster-Waldl, David Medgyesi, Wolf-Dietrich Huber, Jordan S. Orange, Eric Meffre, David M. Sansom, Yenan T. Bryceson, Amnon Altman, and Kaan Boztug. Human def6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant ctla-4 homeostasis. Nature Communications, Jul 2019. URL: https://doi.org/10.1038/s41467-019-10812-x, doi:10.1038/s41467-019-10812-x. This article has 94 citations and is from a highest quality peer-reviewed journal.

  11. (serwas2019humandef6deficiency pages 6-7): Nina K. Serwas, Birgit Hoeger, Rico C. Ardy, Sigrun V. Stulz, Zhenhua Sui, Nima Memaran, Marie Meeths, Ana Krolo, Özlem Yüce Petronczki, Laurène Pfajfer, Tie Z. Hou, Neil Halliday, Elisangela Santos-Valente, Artem Kalinichenko, Alan Kennedy, Emily M. Mace, Malini Mukherjee, Bianca Tesi, Anna Schrempf, Winfried F. Pickl, Joanna I. Loizou, Renate Kain, Bettina Bidmon-Fliegenschnee, Jean-Nicolas Schickel, Salomé Glauzy, Jakob Huemer, Wojciech Garncarz, Elisabeth Salzer, Iro Pierides, Ivan Bilic, Jens Thiel, Peter Priftakis, Pinaki P. Banerjee, Elisabeth Förster-Waldl, David Medgyesi, Wolf-Dietrich Huber, Jordan S. Orange, Eric Meffre, David M. Sansom, Yenan T. Bryceson, Amnon Altman, and Kaan Boztug. Human def6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant ctla-4 homeostasis. Nature Communications, Jul 2019. URL: https://doi.org/10.1038/s41467-019-10812-x, doi:10.1038/s41467-019-10812-x. This article has 94 citations and is from a highest quality peer-reviewed journal.

  12. (manni2017regulationofsystemic pages 6-7): Michela Manni, Edd Ricker, and Alessandra B. Pernis. Regulation of systemic autoimmunity and cd11c+ tbet+ b cells by swef proteins. Cellular immunology, 321:46-51, Nov 2017. URL: https://doi.org/10.1016/j.cellimm.2017.05.010, doi:10.1016/j.cellimm.2017.05.010. This article has 30 citations and is from a peer-reviewed journal.

  13. (binder2017def6restrainsosteoclastogenesis pages 6-8): N. Binder, Christine H. Miller, Masaki Yoshida, Kazuki Inoue, Shinichi Nakano, Xiaoyu Hu, L. Ivashkiv, L. Ivashkiv, G. Schett, Alessandra B. Pernis, Alessandra B. Pernis, S. Goldring, F. Ross, Baohong Zhao, and Baohong Zhao. Def6 restrains osteoclastogenesis and inflammatory bone resorption. The Journal of Immunology, 198:3436-3447, May 2017. URL: https://doi.org/10.4049/jimmunol.1601716, doi:10.4049/jimmunol.1601716. This article has 27 citations.

  14. (binder2017def6restrainsosteoclastogenesis pages 3-4): N. Binder, Christine H. Miller, Masaki Yoshida, Kazuki Inoue, Shinichi Nakano, Xiaoyu Hu, L. Ivashkiv, L. Ivashkiv, G. Schett, Alessandra B. Pernis, Alessandra B. Pernis, S. Goldring, F. Ross, Baohong Zhao, and Baohong Zhao. Def6 restrains osteoclastogenesis and inflammatory bone resorption. The Journal of Immunology, 198:3436-3447, May 2017. URL: https://doi.org/10.4049/jimmunol.1601716, doi:10.4049/jimmunol.1601716. This article has 27 citations.

  15. (serwas2019humandef6deficiency pages 14-15): Nina K. Serwas, Birgit Hoeger, Rico C. Ardy, Sigrun V. Stulz, Zhenhua Sui, Nima Memaran, Marie Meeths, Ana Krolo, Özlem Yüce Petronczki, Laurène Pfajfer, Tie Z. Hou, Neil Halliday, Elisangela Santos-Valente, Artem Kalinichenko, Alan Kennedy, Emily M. Mace, Malini Mukherjee, Bianca Tesi, Anna Schrempf, Winfried F. Pickl, Joanna I. Loizou, Renate Kain, Bettina Bidmon-Fliegenschnee, Jean-Nicolas Schickel, Salomé Glauzy, Jakob Huemer, Wojciech Garncarz, Elisabeth Salzer, Iro Pierides, Ivan Bilic, Jens Thiel, Peter Priftakis, Pinaki P. Banerjee, Elisabeth Förster-Waldl, David Medgyesi, Wolf-Dietrich Huber, Jordan S. Orange, Eric Meffre, David M. Sansom, Yenan T. Bryceson, Amnon Altman, and Kaan Boztug. Human def6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant ctla-4 homeostasis. Nature Communications, Jul 2019. URL: https://doi.org/10.1038/s41467-019-10812-x, doi:10.1038/s41467-019-10812-x. This article has 94 citations and is from a highest quality peer-reviewed journal.

  16. (serwas2019humandef6deficiency pages 5-6): Nina K. Serwas, Birgit Hoeger, Rico C. Ardy, Sigrun V. Stulz, Zhenhua Sui, Nima Memaran, Marie Meeths, Ana Krolo, Özlem Yüce Petronczki, Laurène Pfajfer, Tie Z. Hou, Neil Halliday, Elisangela Santos-Valente, Artem Kalinichenko, Alan Kennedy, Emily M. Mace, Malini Mukherjee, Bianca Tesi, Anna Schrempf, Winfried F. Pickl, Joanna I. Loizou, Renate Kain, Bettina Bidmon-Fliegenschnee, Jean-Nicolas Schickel, Salomé Glauzy, Jakob Huemer, Wojciech Garncarz, Elisabeth Salzer, Iro Pierides, Ivan Bilic, Jens Thiel, Peter Priftakis, Pinaki P. Banerjee, Elisabeth Förster-Waldl, David Medgyesi, Wolf-Dietrich Huber, Jordan S. Orange, Eric Meffre, David M. Sansom, Yenan T. Bryceson, Amnon Altman, and Kaan Boztug. Human def6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant ctla-4 homeostasis. Nature Communications, Jul 2019. URL: https://doi.org/10.1038/s41467-019-10812-x, doi:10.1038/s41467-019-10812-x. This article has 94 citations and is from a highest quality peer-reviewed journal.

  17. (binder2017def6restrainsosteoclastogenesis pages 11-12): N. Binder, Christine H. Miller, Masaki Yoshida, Kazuki Inoue, Shinichi Nakano, Xiaoyu Hu, L. Ivashkiv, L. Ivashkiv, G. Schett, Alessandra B. Pernis, Alessandra B. Pernis, S. Goldring, F. Ross, Baohong Zhao, and Baohong Zhao. Def6 restrains osteoclastogenesis and inflammatory bone resorption. The Journal of Immunology, 198:3436-3447, May 2017. URL: https://doi.org/10.4049/jimmunol.1601716, doi:10.4049/jimmunol.1601716. This article has 27 citations.

  18. (manni2017regulationofsystemic pages 12-14): Michela Manni, Edd Ricker, and Alessandra B. Pernis. Regulation of systemic autoimmunity and cd11c+ tbet+ b cells by swef proteins. Cellular immunology, 321:46-51, Nov 2017. URL: https://doi.org/10.1016/j.cellimm.2017.05.010, doi:10.1016/j.cellimm.2017.05.010. This article has 30 citations and is from a peer-reviewed journal.

  19. (serwas2019humandef6deficiency pages 9-9): Nina K. Serwas, Birgit Hoeger, Rico C. Ardy, Sigrun V. Stulz, Zhenhua Sui, Nima Memaran, Marie Meeths, Ana Krolo, Özlem Yüce Petronczki, Laurène Pfajfer, Tie Z. Hou, Neil Halliday, Elisangela Santos-Valente, Artem Kalinichenko, Alan Kennedy, Emily M. Mace, Malini Mukherjee, Bianca Tesi, Anna Schrempf, Winfried F. Pickl, Joanna I. Loizou, Renate Kain, Bettina Bidmon-Fliegenschnee, Jean-Nicolas Schickel, Salomé Glauzy, Jakob Huemer, Wojciech Garncarz, Elisabeth Salzer, Iro Pierides, Ivan Bilic, Jens Thiel, Peter Priftakis, Pinaki P. Banerjee, Elisabeth Förster-Waldl, David Medgyesi, Wolf-Dietrich Huber, Jordan S. Orange, Eric Meffre, David M. Sansom, Yenan T. Bryceson, Amnon Altman, and Kaan Boztug. Human def6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant ctla-4 homeostasis. Nature Communications, Jul 2019. URL: https://doi.org/10.1038/s41467-019-10812-x, doi:10.1038/s41467-019-10812-x. This article has 94 citations and is from a highest quality peer-reviewed journal.

  20. (manni2017regulationofsystemic pages 3-4): Michela Manni, Edd Ricker, and Alessandra B. Pernis. Regulation of systemic autoimmunity and cd11c+ tbet+ b cells by swef proteins. Cellular immunology, 321:46-51, Nov 2017. URL: https://doi.org/10.1016/j.cellimm.2017.05.010, doi:10.1016/j.cellimm.2017.05.010. This article has 30 citations and is from a peer-reviewed journal.

  21. (binder2017def6restrainsosteoclastogenesis pages 9-11): N. Binder, Christine H. Miller, Masaki Yoshida, Kazuki Inoue, Shinichi Nakano, Xiaoyu Hu, L. Ivashkiv, L. Ivashkiv, G. Schett, Alessandra B. Pernis, Alessandra B. Pernis, S. Goldring, F. Ross, Baohong Zhao, and Baohong Zhao. Def6 restrains osteoclastogenesis and inflammatory bone resorption. The Journal of Immunology, 198:3436-3447, May 2017. URL: https://doi.org/10.4049/jimmunol.1601716, doi:10.4049/jimmunol.1601716. This article has 27 citations.

  22. (biswas2010irf4andits pages 14-15): Partha S. Biswas, Govind Bhagat, and Alessandra B. Pernis. Irf4 and its regulators: evolving insights into the pathogenesis of inflammatory arthritis? Immunological Reviews, 233:79-96, Jan 2010. URL: https://doi.org/10.1111/j.0105-2896.2009.00864.x, doi:10.1111/j.0105-2896.2009.00864.x. This article has 63 citations and is from a domain leading peer-reviewed journal.

  23. (biswas2010irf4andits pages 15-16): Partha S. Biswas, Govind Bhagat, and Alessandra B. Pernis. Irf4 and its regulators: evolving insights into the pathogenesis of inflammatory arthritis? Immunological Reviews, 233:79-96, Jan 2010. URL: https://doi.org/10.1111/j.0105-2896.2009.00864.x, doi:10.1111/j.0105-2896.2009.00864.x. This article has 63 citations and is from a domain leading peer-reviewed journal.

  24. (manni2017regulationofsystemic pages 7-9): Michela Manni, Edd Ricker, and Alessandra B. Pernis. Regulation of systemic autoimmunity and cd11c+ tbet+ b cells by swef proteins. Cellular immunology, 321:46-51, Nov 2017. URL: https://doi.org/10.1016/j.cellimm.2017.05.010, doi:10.1016/j.cellimm.2017.05.010. This article has 30 citations and is from a peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 5
Resolved 5
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 5
On topic 2
Off topic 0

All extracted references resolved successfully.