title: 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.
abstract: 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.
authors.affiliation: Department of Pediatrics, University Medical Center Eppendorf-Hamburg, Hamburg, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: Kobbe
authors.affiliation: Department of Immunology, University Medical Center Eppendorf-Hamburg, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Kolster
authors.affiliation: Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fuchs
authors.affiliation: Department of Pediatrics, University Medical Center Eppendorf-Hamburg, Hamburg, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Schulze-Sturm
authors.affiliation: Labor Lademannbogen, Human Genetics, Hamburg, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Jenderny
authors.affiliation: Labor Lademannbogen, Human Genetics, Hamburg, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Kochhan
authors.affiliation: Department of Psychosomatic Medicine and Psychotherapy, University of Göttingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Staab
authors.affiliation: Department of Immunology, University Medical Center Eppendorf-Hamburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Tolosa
authors.affiliation: Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Germany; Royal Free Hospital, University College London, London, UK; German Center for Infection Research (DZIF), Freiburg.
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.affiliation: Department of Psychosomatic Medicine and Psychotherapy, University of Göttingen, Germany. Electronic address: thomas.meyer@med.uni-goettingen.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
mesh_terms: D002178:Candidiasis, Chronic Mucocutaneous / Q000150:complications / Q000175:diagnosis; D002648:Child; D017074:Common Variable Immunodeficiency / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D065886:Neurodevelopmental Disorders / Q000150:complications / Q000175:diagnosis; D010641:Phenotype; D050794:STAT1 Transcription Factor / Q000235:genetics*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human
keywords: Cytokine signaling; Immunodeficiency; STAT transcription factor; T-regulatory cells