Journal
GENE
Volume 586, Issue 2, Pages 234-238Publisher
ELSEVIER
DOI: 10.1016/j.gene.2016.04.006
Keywords
Immunodeficiency; STAT transcription factor; Cytokine signaling; T-regulatory cells
Categories
Funding
- E-rare program of the European Commission EURO-CMC
- Helmholtz Center [DZIF 8000805-3, TTU IICH 07.80]
- Deutsche Forschungsgemeinschaft [ME1648/7-1]
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Recently, gain-of-function (GOF) mutations in the gene encoding signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis (CMC). This case report describes a 10-year-old boy presenting with signs of common variable immunodeficiency (CVID), failure to thrive, impaired neurological development, and a history of recurrent mucocutaneous Candida infections. Sequencing of the STAT1 gene identified a heterozygous missense mutation in exon 7 encoding the STAT1 coiled-coil domain (c.514T>C, p.Phe172Leu). In addition to hypogammaglobulinemia with B-cell deficiency, and a low percentage of Th17 cells, immunological analysis of the patient revealed a marked depletion of forkhead-box P3(+)-expressing regulatory T cells (Tregs). In vitro stimulation of T cells from the patient with interferon-alpha (IFN alpha) and/or IFN gamma resulted in a significantly increased expression of STAT1-regulated target genes such as MIG1, IRF1, MX1, MCP1/CCL2, IFI-56K, and CXCL10 as compared to IFN-treated cells from a healthy control, while no IFN alpha/gamma-mediated up-regulation of the FOXP3 gene was found. These data demonstrate that the STAT1 GOF mutation F172L, which results in impaired stability of the antiparallel STAT1 dimer conformation, is associated with inhibited Treg cell development and neurological symptoms. (C) 2016 Elsevier B.V. All rights reserved.
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