Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type i interferon signaling
Articolo
Data di Pubblicazione:
2014
Abstract:
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 patients with 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 (MDA5) cause a spectrum of neuro-immunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer a gain-of-function - so 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.
Tipologia CRIS:
1.1 Articolo in rivista
Keywords:
Analysis of Variance; Autoimmune Diseases of the Nervous System; Base Sequence; DEAD-box RNA Helicases; Electrophoretic Mobility Shift Assay; Exome; HEK293 Cells; Humans; Interferon Type I; Microsatellite Repeats; Molecular Sequence Data; Mutation; Nervous System Malformations; Real-Time Polymerase Chain Reaction; Sequence Analysis, DNA; Signal Transduction; Spectrum Analysis; Models, Molecular; Phenotype; Genetics
Elenco autori:
Rice, Gillian I.; Del Toro Duany, Yoandris; Jenkinson, Emma M.; Forte, Gabriella M. A.; Anderson, Beverley H.; Ariaudo, Giada; Bader Meunier, Brigitte; Baildam, Eileen M.; Battini, Roberta; Beresford, Michael W.; Casarano, Manuela; Chouchane, Mondher; Cimaz, Rolando; Collins, Abigail E.; Cordeiro, Nuno J. V.; Dale, Russell C.; Davidson, Joyce E.; De Waele, Liesbeth; Desguerre, Isabelle; Faivre, Laurence; Fazzi, Elisa Maria; Isidor, Bertrand; Lagae, Lieven; Latchman, Andrew R.; Lebon, Pierre; Li, Chumei; Livingston, John H.; Lourenço, Charles M.; Mancardi, Maria Margherita; Masurel Paulet, Alice; Mcinnes, Iain B.; Menezes, Manoj P.; Mignot, Cyril; O'Sullivan, James; Orcesi, Simona; Picco, Paolo P.; Riva, Enrica; Robinson, Robert A.; Rodriguez, Diana; Salvatici, Elisabetta; Scott, Christiaan; Szybowska, Marta; Tolmie, John L.; Vanderver, Adeline; Vanhulle, Catherine; Vieira, Jose Pedro; Webb, Kate; Whitney, Robyn N.; Williams, Simon G.; Wolfe, Lynne A.; Zuberi, Sameer M.; Hur, Sun; Crow, Yanick J.
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