Functional analysis of two STAT1 gain-of-function mutations in two Iranian families with autosomal dominant chronic mucocutaneous candidiasis.


Ostadi V(1), Sherkat R(2), Migaud M(3), Modaressadeghi SM(2), Casanova JL(3)(4)(5)(6), Puel A(3), Nekooie-Marnany N(2), Ganjalikhani-Hakemi M(1)(2).
Author information:
(1)Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
(2)Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
(3)Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Medical School, INSERM U1163 and University Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France, EU.
(4)St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, the Rockefeller University, New York, New York, USA.
(5)Howard Hughes Medical Institute, New York, New York, USA.
(6)Pediatric Hematology-Immunology Unit, Assistance Publique-Hôpitaux de Paris AP-HP, Necker Hospital for Sick Children, Paris, France, EU.


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.