Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in <i>STAT2</i>.

ABSTRACT: Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2^R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2^R148W to interact with ubiquitin

SUBMITTER: Duncan CJA 

PROVIDER: S-EPMC7115903 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature