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

Gillian Rice, Yoandris del Toro Duany, Emma Jenkinson, Gabriella Forte, Beverley Anderson, Giada Ariaudo, Brigitte Bader-Meunier, Eileen M Baildam, Roberta Battini, Michael W Beresford, Manuela Casarano, Mondher Chouchane, Rolando Cimaz, Abigail E Collins, Nuno J V Cordeiro, Russell C Dale, Joyce E Davidson, Liesbeth De Waele, Isabelle Desguerre, Laurence FaivreElisa Fazzi, Bertrand Isidor, Lieven Lagae, Andrew R Latchman, Pierre Lebon, Chumei Li, John H Livingston, Charles M Lourenço, Maria Margherita Mancardi, Alice Masurel-Paulet, Iain B McInnes, Manoj P Menezes, Cyril Mignot, James O'Sullivan, Simona Orcesi, Paolo P Picco, Enrica Riva, Robert A Robinson, Diana Rodriguez, Elisabetta Salvatici, Christiaan Scott, Marta Szybowska, John L Tolmie, Adeline Vanderver, Catherine Vanhulle, Jose Pedro Vieira, Kate Webb, Robyn N Whitney, Simon Williams, Lynne A Wolfe, Sameer M Zuberi, Sun Hur, Yanick Crow

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)503-509
Number of pages6
JournalNature Genetics
Issue number5
Publication statusPublished - May 2014


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