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

Excessive type I interferon (IFN alpha/beta) 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 IFN alpha/beta, 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-specific protease 18, a key STAT2-dependent negative regulator of IFN alpha/beta signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFN alpha/beta signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFN alpha/beta activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.