Van de Veerdonk et al. (2011) evaluated 14 patients from 2 Dutch and 3 British families with autosomal dominant chronic mucocutaneous candidiasis. Mononuclear cells from the affected patients were characterized by poor production of IFNG (147570), IL17 (IL17A; ... Van de Veerdonk et al. (2011) evaluated 14 patients from 2 Dutch and 3 British families with autosomal dominant chronic mucocutaneous candidiasis. Mononuclear cells from the affected patients were characterized by poor production of IFNG (147570), IL17 (IL17A; 603149), and IL22 (605330). In addition to candidiasis, the 67-year-old father of one of the Dutch families had autoimmune hepatitis, and his 38-year-old daughter had autoimmune hemolytic anemia and anti-phospholipid antibodies; his 37-year-old son had candidiasis but no autoimmune phenomena. The father and daughter also suffered from chest infections, and the daughter had pulmonary embolism and Pneumocystis jirovecii pneumonia with symptomatic cytomegalovirus infection. None of the other families exhibited autoimmune disease, but members of 2 of the British families also suffered from chest infections. One member of the second Dutch family, as well as her deceased mother, and members of 2 British families had esophageal or oral carcinoma. Members of all 3 British families also had hypothyroidism.
In 2 Dutch and 3 British families with autosomal dominant chronic mucocutaneous candidiasis, van de Veerdonk et al. (2011) identified 2 heterozygous mutations in exon 10 of the STAT1 gene. Both mutations, arg274 to trp (R274W; 600555.0008) and ... In 2 Dutch and 3 British families with autosomal dominant chronic mucocutaneous candidiasis, van de Veerdonk et al. (2011) identified 2 heterozygous mutations in exon 10 of the STAT1 gene. Both mutations, arg274 to trp (R274W; 600555.0008) and ala267 to val (A267V; 600555.0009), occurred in the coiled-coil domain of STAT1 and resulted in defective responses in Th1 and Th17 cells, characterized by poor production of IFNG, IL17, and IL22 (605330). Liu et al. (2011) identified 12 missense mutations in exons 6 through 10 of the STAT1 gene in 36 patients from 20 kindreds with autosomal dominant chronic mucocutaneous candidiasis. All 12 mutations affected a cluster of residues in a specific pocket of the STAT1 coiled-coil domain, near residues essential for dephosphorylation. Extensive functional characterization revealed that at least 11 of the 12 candidiasis-associated STAT1 mutations were gain of function, with enhanced induction of GAS binding in response to IFNG, IFNA (147660), or IL27 (608273). Studies with the arg274-to-gln (R274Q; 600555.0010) and asp165-to-gly (D165G; 600555.0014) mutations showed that the gain-of-function mechanism involved increased phosphorylation of tyr701 of STAT1 due to impaired nuclear dephosphorylation. Patients with STAT1 gain-of-function mutations had lower proportions of circulating IL17A- and IL22-producing T cells and lower secretion of IL17A, IL17F (606496), and IL22 compared with healthy controls and patients with STAT1 loss-of-function alleles, such as leu706 to ser (L706S; 600555.0001). Liu et al. (2011) concluded that patients with familial or sporadic autosomal dominant chronic mucocutaneous candidiasis and mutations affecting the coiled-coil domain of STAT1 produce lower amounts of IL17, which renders them susceptible to extracellular fungal disease. By cloning and transfection experiments, Smeekens et al. (2011) found that the R274Q mutation underlying CANDF7 inhibited IL12R (see 601604)/IL23R (607562) signaling, likely due to STAT1 hyperphosphorylation. Inhibition of IL12R/IL23R signaling led to diminished Th1/Th17 responses and increased susceptibility to fungal infections.