Common variable immunodeficiency, impaired neurological development and reduced numbers of T regulatory cells in a 10-year-old boy with a STAT1 gain-of-function mutation

• Published in: Gene 2016-07, Vol.586 (2), p.234-238
• Main Authors: Kobbe, Robin, Kolster, Manuela, Fuchs, Sebastian, Schulze-Sturm, Ulf, Jenderny, Jutta, Kochhan, Lothar, Staab, Julia, Tolosa, Eva, Grimbacher, Bodo, Meyer, Thomas
• Format: Article
• Language: English
• Subjects: Candida; Candidiasis, Chronic Mucocutaneous - complications; Candidiasis, Chronic Mucocutaneous - diagnosis; Child; Common Variable Immunodeficiency - complications; Common Variable Immunodeficiency - diagnosis; Common Variable Immunodeficiency - genetics; Common Variable Immunodeficiency - immunology; Cytokine signaling; Gene Expression; Humans; Immunodeficiency; Male; Mutation, Missense; Neurodevelopmental Disorders - complications; Neurodevelopmental Disorders - diagnosis; Phenotype; STAT transcription factor; STAT1 Transcription Factor - genetics; T-Lymphocytes, Regulatory - immunology; T-regulatory cells
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2016.04.006

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-α (IFNα) and/or IFNɣ 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 IFNα/ɣ-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. •A STAT1 Phe172Leu gain-of-function mutation is associated with low T regulatory cells.•Proliferation of T cells in response to anti-CD3 and IL-2 was unaltered.•The index patient presents with signs of common variable immunodeficiency (CVID).•The mutation carrier suffers from dystrophy and delayed neurocognitive development.