STAT2 deficiency and susceptibility to viral illness in humans

Sophie Hambleton, Stephen Goodbourn, Dan F Young, Paul Dickinson, Siti M B Mohamad, Manoj Valappil, Naomi McGovern, Andrew J Cant, Scott J Hackett, Peter Ghazal, Neil V Morgan, Richard E Randall

Research output: Contribution to journalArticlepeer-review

119 Citations (Scopus)


Severe infectious disease in children may be a manifestation of primary immunodeficiency. These genetic disorders represent important experiments of nature with the capacity to elucidate nonredundant mechanisms of human immunity. We hypothesized that a primary defect of innate antiviral immunity was responsible for unusually severe viral illness in two siblings; the proband developed disseminated vaccine strain measles following routine immunization, whereas an infant brother died after a 2-d febrile illness from an unknown viral infection. Patient fibroblasts were indeed abnormally permissive for viral replication in vitro, associated with profound failure of type I IFN signaling and absence of STAT2 protein. Sequencing of genomic DNA and RNA revealed a homozygous mutation in intron 4 of STAT2 that prevented correct splicing in patient cells. Subsequently, other family members were identified with the same genetic lesion. Despite documented infection by known viral pathogens, some of which have been more severe than normal, surviving STAT2-deficient individuals have remained generally healthy, with no obvious defects in their adaptive immunity or developmental abnormalities. These findings imply that type I IFN signaling [through interferon-stimulated gene factor 3 (ISGF3)] is surprisingly not essential for host defense against the majority of common childhood viral infections.

Original languageEnglish
Pages (from-to)3053-8
Number of pages6
JournalNational Academy of Sciences. Proceedings
Issue number8
Publication statusPublished - 19 Feb 2013


  • Base Sequence
  • Cells, Cultured
  • Child, Preschool
  • DNA Primers
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Interferon Type I
  • Oligonucleotide Array Sequence Analysis
  • Pedigree
  • RNA, Messenger
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT2 Transcription Factor
  • Virus Diseases


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