Chronic mucocutaneous candidiasis caused by a gain-of-function mutation in the STAT1 DNA-binding domain.
Chronic mucocutaneous candidiasis (CMC) is a heterogeneous group of primary immunodeficiency diseases characterized by chronic and recurrent Candida infections of the skin, nails, and oropharynx. Gain-of-function mutations in STAT1 were very recently shown to be responsible for autosomal-dominant or sporadic cases of CMC. The reported mutations have been exclusively localized in the coiled-coil domain, resulting in impaired dephosphorylation of STAT1. However, recent crystallographic analysis and direct mutagenesis experiments indicate that mutations affecting the DNA-binding domain of STAT1 could also lead to persistent phosphorylation of STAT1. To our knowledge, this study shows for the first time that a DNA-binding domain mutation of c.1153C>T in exon 14 (p.T385M) is the genetic cause of sporadic CMC in two unrelated Japanese patients. The underlying mechanisms involve a gain of STAT1 function due to impaired dephosphorylation as observed in the coiled-coil domain mutations.
Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
Shunichiro
S
Takezaki
Masafumi
M
Yamada
Masahiko
M
Kato
Myoung-Ja
MJ
Park
Kenichi
K
Maruyama
Yasuhiro
Y
Yamazaki
Natsuko
N
Chida
Osamu
O
Ohara
Ichiro
I
Kobayashi
Tadashi
T
Ariga
D000293:Adolescent; D000595:Amino Acid Sequence; D044466:Asian People; D002178:Candidiasis, Chronic Mucocutaneous / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D002461:Cell Line, Transformed; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics / Q000276:immunology*; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics*
D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human