Alt. symbols: IBP | SLAT | SWAP70L

Approved name: DEF6 guanine nucleotide exchange factor
Alt. names: differentially expressed in FDCP (mouse homolog) 6, differentially expressed in FDCP 6 homolog (mouse) | SWAP-70-like adaptor protein of T cells

Location: 6p21.31: 35297818 - 35321771 (+)
Gene type: protein_coding, 6 transcripts.

Scores: LoFtool: 0.280000 | pLI: 0.97682415 | LOEUF: 0.259

HGNC: 2760

NCBI: 50619, RefSeq: .0

Ensembl: ENSG00000023892.12

LRG_ | Status: none

OMIM: 610094

Expression | ProteinAtlas

DEF6 encodes a phosphatidylinositol 3,4,5-trisphosphate-dependent guanine nucleotide exchange factor (GEF) that plays a role in the activation of Rho GTPases RAC1, RhoA and CDC42. It can regulate cell morphology in cooperation with activated RAC1. It is believed to play a role in Th2 (T helper cells) development and/or activation, perhaps by interfering with ZAP70 signaling.

Bi-allelic missense and nonsense loss-of-function mutations in DEF6 have been reported for an autosomal recessive syndrome of immunodeficiency and autoimmunity [MIM: 619573] by two groups. Serwas et al. (2019) identified 2 homozygous DEF6 missense variants (Glu331Lys and Tyr210Asp) in 3 patients from 2 consanguineous families with increased infection susceptibility and early onset systemic autoimmunity (PMID: 31308374). The authors showed that both variants resulted in reduced protein expression , as well as impaired intracellular CTLA-4 trafficking and surface presentation. Immunoglobulin levels were not consistently altered but only few CD19+CD27+IgD- class-switched B cells were detected and specific antibody responses were impaired. Fournier et al. (2021) then identified a homozygous nonsense variant (c.940C>T, p.Gln314Ter) associated with absent DEF6 protein expression in 4 members of a consanguineous family with autoimmunity and EBV susceptibility, but no recurrent infections (PMID: 32562707). Moreover, immunoglobulin levels and peripheral B-cell subset levels were normal. However, the centrality of aberrant CTLA-4 transport to the mechanism of DEF6-related disease and the phenotypic overlap with CTLA-4 haploinsufficiency suggests that additional mutations in DEF6 have the potential to cause a CVID-like phenotype with humoral immune defects (PMID: 34153571). [Load More]