STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis

Area of Science:

• Immunology
• Genetics
• Dermatology

Background:

• Chronic mucocutaneous candidiasis (CMC) involves susceptibility to Candida infections affecting skin, nails, and mucous membranes.
• Recessive CMC with autoimmunity is linked to AIRE gene mutations; the cause of autosomal dominant CMC remained unknown.

Purpose of the Study:

• To investigate the genetic basis of autosomal dominant chronic mucocutaneous candidiasis (CMC).
• To identify the molecular defect responsible for impaired immune responses in patients with dominant CMC.

Main Methods:

• Evaluated 14 patients from five families with autosomal dominant CMC.
• Assessed immune cell function and utilized next-generation sequencing to identify genetic mutations.
• Focused on genes involved in immune pathway signaling.

Main Results:

• Patients exhibited poor production of interferon-gamma, interleukin-17, and interleukin-22.
• Identified heterozygous missense mutations in the coiled-coil (CC) domain of signal transducer and activator of transcription 1 (STAT1).
• These STAT1 mutations resulted in defective type 1 and type 17 helper T-cell responses.

Conclusions:

• Mutations in the STAT1 CC domain are the cause of autosomal dominant CMC.
• Defective STAT1 signaling impairs Th1 and Th17 cell responses, leading to fungal susceptibility.
• Findings elucidate a novel genetic cause for a subset of CMC patients.