Gain-of-function mutations in STAT1: A new molecular cause for patients with chronic mucocutaneous candidiasis

Abstract

Background: Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of skin, nails or mucosa with candida species. Most of the cases are sporadic; however, both autosomal dominant and autosomal recessive inheritance has been reported. Recent research suggests that autosomal dominant CMC may be due to heterozygous gain-of-function mutations in the signalling protein STAT1. Methods: We studied twelve unrelated families with autosomal dominant CMC and ten sporadic patients. We sequenced the genomic DNA of affected individuals, searching for heterozygous mutations in the 15 exons covering the coiled-coil and DNA-binding domain of STAT1. Results: After performing Sanger sequencing on all patients, we identified five different missense mutations in the coiled-coil domain of STAT1 in eight of the twelve CMC families. We then focused on sequencing the sporadic cases. In three of ten sporadic CMC patients we identified heterozygous missense mutation in the DNA-binding domain of STAT1. Conclusion: Missense mutations in the coiled-coil and DNA-binding domain of STAT1 may be the cause for sporadic and autosomal dominant CMC. Thus, STAT1 has to be taken into account when diagnosing this condition. The mutations we report are gain-of-function mutations. Interestingly, loss-of-function mutations in STAT1 lead to the susceptibility to mycobacterial and viral diseases.