Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

J Exp Med. 2020 May 4;217(5):e20192319. doi: 10.1084/jem.20192319.

Abstract

Type I interferonopathies are monogenic disorders characterized by enhanced type I interferon (IFN-I) cytokine activity. Inherited USP18 and ISG15 deficiencies underlie type I interferonopathies by preventing the regulation of late responses to IFN-I. Specifically, USP18, being stabilized by ISG15, sterically hinders JAK1 from binding to the IFNAR2 subunit of the IFN-I receptor. We report an infant who died of autoinflammation due to a homozygous missense mutation (R148Q) in STAT2. The variant is a gain of function (GOF) for induction of the late, but not early, response to IFN-I. Surprisingly, the mutation does not enhance the intrinsic activity of the STAT2-containing transcriptional complex responsible for IFN-I-stimulated gene induction. Rather, the STAT2 R148Q variant is a GOF because it fails to appropriately traffic USP18 to IFNAR2, thereby preventing USP18 from negatively regulating responses to IFN-I. Homozygosity for STAT2 R148Q represents a novel molecular and clinical phenocopy of inherited USP18 deficiency, which, together with inherited ISG15 deficiency, defines a group of type I interferonopathies characterized by an impaired regulation of late cellular responses to IFN-I.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Cell Line
  • Exome Sequencing
  • Female
  • Gain of Function Mutation / genetics*
  • Gene Expression Regulation
  • Homozygote
  • Humans
  • Infant, Newborn
  • Interferon Type I / metabolism*
  • Male
  • Pedigree
  • Phenotype
  • Protein Domains
  • STAT2 Transcription Factor / chemistry
  • STAT2 Transcription Factor / genetics*
  • Ubiquitin Thiolesterase / deficiency*
  • Ubiquitin Thiolesterase / genetics

Substances

  • Interferon Type I
  • STAT2 Transcription Factor
  • STAT2 protein, human
  • USP18 protein, human
  • Ubiquitin Thiolesterase