Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling

Nat Genet. 2014 May;46(5):503-509. doi: 10.1038/ng.2933. Epub 2014 Mar 30.


The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Autoimmune Diseases of the Nervous System / genetics*
  • Autoimmune Diseases of the Nervous System / immunology
  • Base Sequence
  • DEAD-box RNA Helicases / chemistry
  • DEAD-box RNA Helicases / genetics*
  • Electrophoretic Mobility Shift Assay
  • Exome / genetics
  • HEK293 Cells
  • Humans
  • Interferon Type I / immunology*
  • Interferon-Induced Helicase, IFIH1
  • Microsatellite Repeats / genetics
  • Models, Molecular*
  • Molecular Sequence Data
  • Mutation / genetics*
  • Nervous System Malformations / genetics*
  • Nervous System Malformations / immunology
  • Phenotype*
  • Real-Time Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Signal Transduction / genetics*
  • Spectrum Analysis


  • Interferon Type I
  • IFIH1 protein, human
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1

Supplementary concepts

  • Aicardi-Goutieres syndrome