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. 2011 Jul 7;365(1):54-61.
doi: 10.1056/NEJMoa1100102. Epub 2011 Jun 29.

STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis

Frank L van de Veerdonk  1 , Theo S Plantinga, Alexander Hoischen, Sanne P Smeekens, Leo A B Joosten, Christian Gilissen, Peer Arts, Diana C Rosentul, Andrew J Carmichael, Chantal A A Smits-van der Graaf, Bart Jan Kullberg, Jos W M van der Meer, Desa Lilic, Joris A Veltman, Mihai G Netea
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Free article

STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis

Frank L van de Veerdonk et al. N Engl J Med. .
Free article

Abstract

Background: Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to candida infection of skin, nails, and mucous membranes. Patients with recessive CMC and autoimmunity have mutations in the autoimmune regulator AIRE. The cause of autosomal dominant CMC is unknown.

Methods: We evaluated 14 patients from five families with autosomal dominant CMC. We incubated their peripheral-blood mononuclear cells with different combinations of stimuli to test the integrity of pathways that mediate immunity, which led to the selection of 100 genes that were most likely to contain the genetic defect. We used an array-based sequence-capture assay, followed by next-generation sequencing, to identify mutations.

Results: The mononuclear cells from the affected patients were characterized by poor production of interferon-γ, interleukin-17, and interleukin-22, suggesting that the defect lay within the interleukin-12 receptor and interleukin-23 receptor signaling pathways. We identified heterozygous missense mutations in the DNA sequence encoding the coiled-coil (CC) domain of signal transducer and activator of transcription 1 (STAT1) in the patients. These mutations lead to defective responses in type 1 and type 17 helper T cells (Th1 and Th17). The interferon-γ receptor pathway was intact in these patients.

Conclusions: Mutations in the CC domain of STAT1 underlie autosomal dominant CMC and lead to defective Th1 and Th17 responses, which may explain the increased susceptibility to fungal infection. (Funded by the Netherlands Organization for Scientific Research and others.).

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