Genetic and Functional Identifying of Novel Autosomal Dominant STAT1 Loss-of-function Mutations in Patients with Diverse Clinical Phenotypes

Abstract Purpose Mutations in Signal transducer and activator of transcription 1 (STAT1) cause a broad spectrum of disease phenotypes. Heterozygous STAT1 loss-of-function (LOF) mutations cause Mendelian susceptibility to mycobacterial diseases (MSMD) and Salmonella infection, both of which are attributable to impaired IFN-γ signaling. The identification of novel mutations may extend the phenotypes associated with autosomal dominant (AD) STAT1 deficiency.Methods Seven patients with heterozygous STAT1 variations were recruited and their clinical and immunologic phenotypes were analyzed, with particular reference to JAK-STAT1 signaling pathways.Results Five, heterozygous STAT1-deficiency mutations were identified, four of which were novel mutations. Two of the mutations were previously unreported mRNA splicing mutations in AD STAT1 deficient patients. Patients with heterozygous STAT1 deficiency suffered not only mycobacterial infection, but also Candida albicans infection and congenital multiple malformations. AD-LOF mutation impaired IFN-γ mediated STAT1 phosphorylation, gamma-activated sequence (GAS) and IFN-stimulated response element (ISRE) transcription activity and IFN-induced gene expression to different extents, which might account for the diverse clinical manifestations observed in these patients.Conclusion Aberrant splice of STAT1 RNA resulted in AD-LOF for STAT1 signaling. The infectious disease susceptibility and phenotypic spectrum of patients with AD STAT1-LOF are broader than simply MSMD and could overlap with AD STAT1-GOF mutation phenotypes. The susceptibility to infections and immunological deficiency phenotypes, observed in AD-LOF patients, confirms the importance of STAT1 in host-pathogen interaction and immunity. However, variability in the nature and extent of these phenotypes suggests that functional analysis is required to identify accurately novel, heterozygous STAT1 mutations, associated with pathogenicity.