Abstract
PurposeGain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients.MethodsSTAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients’ peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients.ResultsHeterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61 %). Out of 39 familial cases from 11 families, 26 patients (67 %) from 9 families and out of 18 sporadic cases, 9 patients (50 %) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients.ConclusionSTAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.
Highlights
Chronic mucocutaneous candidiasis (CMC) constitutes a collective term for a heterogeneous group of syndromes with the common feature of chronic non-invasive Candida infections of the skin, nails and mucous membranes, primarily with Candida albicans
signal transducer and activator of transcription 1 (STAT1) mutations are frequently observed in patients suffering from CMC
The majority of GOF-STAT1 mutations are confined to the coiledcoil domain (CCD) of STAT1, several other GOF mutations have been found in the DNA-binding domain (DBD) [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33]
Summary
Chronic mucocutaneous candidiasis (CMC) constitutes a collective term for a heterogeneous group of syndromes with the common feature of chronic non-invasive Candida infections of the skin, nails and mucous membranes, primarily with Candida albicans. CMC presents heterogeneously both in clinical manifestations and genetic background, studies conducted so far emphasize the key role of T helper 17 (Th17) cells and the impaired effector function of their cytokines interleukin 17 (IL-17) and interleukin 22 (IL-22) These cytokines have been shown to be essential for mucocutaneous anti-fungal host defense [5,6,7]. Patients with autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy (APECED)-syndrome bearing biallelic mutations in the autoimmune regulator (AIRE) gene are as well susceptible to Candida infections but no other pathogens. These patients have high titers of neutralizing autoantibodies against IL-17A, IL-17F and IL-22 [13,14,15]. We compiled an in depth description of the STAT1 clinical CMC phenotype in order to provide a clear clinical picture for this condition
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