Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling
Affiliation auteurs | !!!! Error affiliation !!!! |
Titre | Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling |
Type de publication | Journal Article |
Year of Publication | 2014 |
Auteurs | Rice GI, Duany Ydel Toro, Jenkinson EM, Forte GMA, Anderson BH, Ariaudo G, Bader-Meunier B, Baildam EM, Battini R, Beresford MW, Casarano M, Chouchane M, Cimaz R, Collins AE, Cordeiro NJV, Dale RC, Davidson JE, De Waele L, Desguerre I, Faivre L, Fazzi E, Isidor B, Lagae L, Latchman AR, Lebon P, Li C, Livingston JH, Lourenco CM, Mancardi MMargherita, Masurel-Paulet A, McInnes LB, Menezes MP, Mignot C, O'Sullivan J, Orcesi S, Picco PP, Riva E, Robinson RA, Rodriguez D, Salvatici E, Scott C, Szybowska M, Tolmie JL, Vanderver A, Vanhulle C, Vieira JPedro, Webb K, Whitney RN, Williams SG, Wolfe LA, Zuberi SM, Hur S, Crow YJ |
Journal | NATURE GENETICS |
Volume | 46 |
Pagination | 503-509 |
Date Published | MAY |
Type of Article | Article |
ISSN | 1061-4036 |
Résumé | 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-Goutieres 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. |
DOI | 10.1038/ng.2933 |