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

Nat Genet 2014 May 30;46(5):503-509. Epub 2014 Mar 30.

Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK.

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.

Download full-text PDF

Source
http://www.idi.harvard.edu/uploads/investigators/YoaNatureGe
Web Search
http://www.nature.com/doifinder/10.1038/ng.2933
Publisher Site
http://dx.doi.org/10.1038/ng.2933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004585PMC
May 2014
171 Reads

Publication Analysis

Top Keywords

type interferon
12
upregulated type
8
interferon signaling
8
interferon
5
immunological phenotypes
4
rna avidly
4
phenotypes demonstrating
4
demonstrating upregulated
4
heterozygous mutations
4
ifih1 binds
4
response heterozygous
4
binds rna
4
interferon response
4
neurological immunological
4
undefined neurological
4
uncharacterized cases
4
cases type
4
genetically uncharacterized
4
biochemical assays
4
ligand-induced interferon
4

Similar Publications