ClinVar

In an affected brother and sister from a consanguineous Algerian family with chronic mucocutaneous candidiasis (CANDF8; 615527), Boisson et al. (2013) identified homozygosity for a c.1607C-T transition in the TRAF3IP2 gene, resulting in a thr536-to-ile (T536I) substitution at a highly conserved residue in the C-terminal part of the SEFIR domain. The mutation, which segregated with disease in the family, was not found in more than 10,000 chromosomes or in the 1000 Genomes Project or dbSNP (build 135) databases. Neither of the affected sibs displayed psoriasis. Functional analysis using patient fibroblasts and EBV-B cells demonstrated that the T536I mutant abolishes homotypic interactions with the SEFIR domain of IL17RA (605461), IL17RB (605458), and IL17RC (610925), but does not affect homodimerization or SEFIR-independent ACT1 interactions with other proteins. Patient fibroblasts did not produce IL6 (147620) in response to IL17A (603149) or IL17F (606496). Stimulation of patient peripheral blood mononuclear cells with IL2 (147680) and/or IL17E (605658) resulted in production of IL5 (147850) only in response to IL2, and there was no synergistic response to costimulation. Flow cytometric analysis indicated that the patients had higher proportions of IL17- and IL22 (605330)-producing cells but normal levels of IFNG (147570)-producing cells, suggesting that responsiveness to IL17 rather than production of the cytokine is critical for protection from chronic mucocutaneous candidiasis.