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.
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We sincerely thank the participating families for the use of genetic samples and clinical information and all clinicians who contributed samples and data not included in this manuscript. We thank D. Chase for proofreading the manuscript. We thank G. Notarangelo for helpful discussion. Y.d.T.D. holds a Novartis Foundation postdoctoral fellowship. S.H. holds a Pew scholarship and Career Development award from Boston Children's Hospital. Y.J.C. acknowledges the Manchester Biomedical Research Centre, Manchester Academic Health Sciences Centre, the Greater Manchester Comprehensive Local Research Network, the Great Ormond Street Hospital Children's Charity, the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement 241779 and the European Research Council (GA 309449). The authors would like to thank the NHLBI GO ESP and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the Women's Health Initiative (WHI) Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).
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Supplementary Note, Supplementary Figures 1–4 and Supplementary Tables 1–7
About this article
Frontiers in Cell and Developmental Biology (2019)