Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

Abstract

Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guérin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

“…P2 and P4 were also treated for suspected pulmonary tuberculosis and tuberculous meningitis, respectively, without microbiological confirmation. None of the other clinical manifestations previously reported in patients with GOF STAT1 mutations, such as autoimmune endocrinopathy, aneurysms, or mucosal carcinomas, were detected (16,17,23,37,51). Detailed phenotyping of lymphocyte subsets was performed for patients from kindreds D, E, and H and revealed no abnormality (Fig.…”

“…In patients with STAT1 GOF mutations, CMC results, at least partly, from impairment of the development and/or survival of IL-17A/F-producing T cells, the underlying mechanisms of which remain unknown (28,52). Patients with these mutations, who had long been known to be prone to thyroid autoimmunity, were recently found to display other infectious and autoimmune phenotypes (16,17,23,37,51). Another genetic etiology of syndromic CMCD has recently been described, with AR retinoic acid-related orphan receptors γ (ROR-γ/γT) deficiency in three kindreds with CMC and severe mycobacterial disease (53).…”

Molecular mechanism and structural basis of gain-of-function of STAT1 caused by pathogenic R274Q mutation

“…On the other hand, its gain-of-function (GOF) mutations exhibit different immunological defects. The patients suffer from persistent or recurrent infection of the skin, nails, and mucous membranes with Candida albicans, referred to as chronic mucocutaneous candidiasis (CMC) (7)(8)(9). Assigning structural changes caused by these pathogenic amino acid substitutions has shed light on the molecular mechanisms of STAT1-mediated immunodeficiencies as well as the fundamental roles of the original residue in normal STAT1 functions.…”

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

“…Notably, AIRE-and STAT1-mutant CMC patients are susceptible to developing oral, esophageal, and stomach carcinomas. [59][60][61][62] APECED is a rare disease but is more prevalent among some populations, such as Finns (1/25 000), Sardinians (1/14 400), and Iranian Jews (1/9000). [63][64][65] More than 60 AIRE mutations have been reported in APECED.…”

“…These mutations include D165G, D165H, Y170N, F172S, C174R, N179K, M202V, M202T, A267V, R274Q, R274W, R274Q, K286I, Q285R, T288A, P329L, N357D, T385M, K388E, and T437I, which inactivate the DNA-binding and coiledcoil functions of STAT1 but increase its phosphorylation. [55,56,61,62,77,78] These patients develop autoimmunity, persistent, or recurrent fungal infection, and gastrointestinal tract (GI) cancers found in the oral cavity, esophagus, and stomach ( Table 2).…”