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Publication year
2011Source
The New England Journal of Medicine, 365, 1, (2011), pp. 54-61ISSN
Publication type
Article / Letter to editor

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Organization
Internal Medicine
Human Genetics
Pulmonary Diseases
Journal title
The New England Journal of Medicine
Volume
vol. 365
Issue
iss. 1
Page start
p. 54
Page end
p. 61
Subject
N4i 1: Pathogenesis and modulation of inflammation; N4i 2: Invasive mycoses and compromised host NCMLS 1: Infection and autoimmunity; N4i 3: Poverty-related infectious diseases ONCOL 5: Aetiology, screening and detection; NCMLS 6: Genetics and epigenetic pathways of disease IGMD 3: Genomic disorders and inherited multi-system disordersAbstract
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-gamma, 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-gamma 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.).
This item appears in the following Collection(s)
- Academic publications [227902]
- Electronic publications [107427]
- Faculty of Medical Sciences [86234]
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