1. Functional analysis of two STAT1 gain-of-function mutations in two Iranian families with autosomal dominant chronic mucocutaneous candidiasis
- Author
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Anne Puel, Nioosha Nekooie-Marnany, Jean-Laurent Casanova, Mélanie Migaud, Seyed-Mehran Modaressadeghi, Mazdak Ganjalikhani-Hakemi, Vajiheh Ostadi, and Roya Sherkat
- Subjects
Male ,Adolescent ,T cell ,Gene Expression ,Iran ,Mucocutaneous Candidiasis ,medicine.disease_cause ,Peripheral blood mononuclear cell ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Antigen ,Interferon ,medicine ,Humans ,Family ,Chronic mucocutaneous candidiasis ,Phosphorylation ,Candida albicans ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Mutation ,biology ,business.industry ,Candidiasis, Chronic Mucocutaneous ,Interleukin-17 ,General Medicine ,medicine.disease ,biology.organism_classification ,Flow Cytometry ,Infectious Diseases ,medicine.anatomical_structure ,STAT1 Transcription Factor ,Child, Preschool ,Gain of Function Mutation ,Immunology ,Th17 Cells ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Candidiasis is characterized by susceptibility to recurrent or persistent infections caused by Candida spp., typically Candida albicans, of cutaneous and mucosal surfaces. In this report, function and frequency of Th17 cells as well as genetics of patients susceptible to mucocutaneous candidiasis were studied. For patients, T-cell proliferation tests in response to Candida antigen, Th17 cell proportions, and STAT1 phosphorylation were evaluated through flow cytometry. Expression of IL17A, IL17F and IL22 genes were measured by real-time quantitative PCR. At the same time, whole exome sequencing was performed for all patients. We identified two heterozygous substitutions, one: c.821G > A (p. R274Q) was found in a multiplex family with three individuals affected, the second one: c.812A > C (p. Q271P) was found in a sporadic case. Both mutations are located in the coiled-coil domain (CCD) of STAT1. The frequency of Th17 cells, IL17A, IL17F, and IL22 gene expression in patients’ peripheral blood mononuclear cells (PBMCs), and T-cell proliferation to Candida antigens were significantly reduced in the patients as compared to healthy controls. An increased STAT1 phosphorylation was observed in patients’ PBMCs upon interferon (IFN)-γ stimulation as compared to healthy controls. We report two different but neighboring heterozygous mutations, located in exon 10 of the STAT1 gene, in four Iranian patients with CMC, one of whom also had hypothyroidism. These mutations were associated with impaired T cell proliferation to Candida antigen, low Th17 cell proportions, and increased STAT1 phosphorylation upon IFN-γ. We suggest that interfering with STAT1 phosphorylation might be a promising way for potential therapeutic measurements for such patients.
- Published
- 2019