Inborn errors of immunity with loss- and gain-of-function germline mutations in STAT1.

Abstract

Signal transducer and activator of transcription 1 (STAT1) is a well-known and pivotal molecule in the regulation of the Janus activating kinases (JAK)-STAT pathway, an extensive signalling pathway downstream of several cytokine receptors that plays an indispensable role in immune defence in humans. In the JAK-STAT pathway, STAT1 homodimer-dependent IFN-γ immunity is crucial for defence against intra-macrophagic bacteria, and STAT1/STAT2/IRF9 complex-dependent IFN-α/β immunity is essential for protection against viruses. STAT1 dysfunction causes a wide range of immune dysregulation phenotypes, which have been classified into four disease types, namely, (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD STAT1 gain-of-function (GOF), based on their mode of inheritance and function. Disease types (i, ii, and iii) are caused by STAT1 loss-of-function (LOF) mutations, whereas disease type (iv) is caused by STAT1 GOF mutations. Notably, rapid and accurate diagnosis of these four diseases can be difficult. In particular, the differential diagnosis of AD STAT1 deficiency and AD STAT1 GOF, which are caused by LOF- and GOF-STAT1 mutations, respectively, can be complicated due to their overlapping clinical symptoms. In addition, more than 150 pathological mutations have been identified in STAT1 across all domains, making functional prediction of novel mutations difficult. Thus, the functional analysis of mutations is necessary for diagnosis. The recently proposed reference database of mutant STAT1 functions based on comprehensive alanine scanning is a useful tool for evaluating unknown STAT1 mutations with high accuracy.