Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency

Nat Genet. 2003 Mar;33(3):388-91. doi: 10.1038/ng1097. Epub 2003 Feb 18.


The receptors for interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma activate components of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, leading to the formation of at least two transcription factor complexes. STAT1 interacts with STAT2 and p48/IRF-9 to form the transcription factor IFN-stimulated gene factor 3 (ISGF3). STAT1 dimers form gamma-activated factor (GAF). ISGF3 is induced mainly by IFN-alpha/beta, and GAF by IFN-gamma, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-gamma receptor (IFN-gammaR) are susceptible to infection with mycobacteria. A heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease. No individuals with deleterious mutations in the IFN-alpha/beta signaling pathway have been described. We report here two unrelated infants homozygous with respect to mutated STAT1 alleles. Neither IFN-alpha/beta nor IFN-gamma activated STAT1-containing transcription factors. Like individuals with IFN-gammaR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-gammaR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-alpha/beta in cell lines from the two individuals. Inherited impairment of the STAT1-dependent response to human IFN-alpha/beta thus results in susceptibility to viral disease.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Antiviral Agents / pharmacology
  • Base Sequence
  • Consanguinity
  • DNA / genetics
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics*
  • Female
  • Humans
  • In Vitro Techniques
  • Infant
  • Interferon Type I / pharmacology*
  • Interferon-gamma / pharmacology*
  • Male
  • Mycobacterium Infections / drug therapy
  • Mycobacterium Infections / etiology
  • Mycobacterium Infections / genetics
  • Mycobacterium Infections / physiopathology
  • Pedigree
  • Recombinant Proteins
  • STAT1 Transcription Factor
  • Sequence Deletion
  • Signal Transduction
  • Trans-Activators / deficiency*
  • Trans-Activators / genetics*
  • Virus Diseases / drug therapy
  • Virus Diseases / etiology*
  • Virus Diseases / genetics
  • Virus Diseases / physiopathology


  • Antiviral Agents
  • DNA-Binding Proteins
  • Interferon Type I
  • Recombinant Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Trans-Activators
  • Interferon-gamma
  • DNA