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

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 a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, which manifest as prolonged Janus kinase-signal transducers and activators of transcription signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant duanyu18132^R148W to interact with ubiquitin-specific protease 18, a key negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}