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

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 STAT2R148Win homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, manifest as prolonged JAK-STAT signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148Wto interact with ubiquitin specific protease 18 (USP18), a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivofunction of STAT2 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