Portal de Periódicos da CAPES

Artigo Acesso aberto Produção Nacional Revisado por pares

BIBTEX RIS

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

2014; Nature Portfolio; Volume: 46; Issue: 5 Linguagem: Inglês

10.1038/ng.2933

1546-1718

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

Cytokine Signaling Pathways and Interactions

Yanick Crow, Sun Hur and colleagues show that gain-of-function mutations in IFIH1 cause a spectrum of neural and immunological phenotypes associated with enhanced interferon signaling. The mutations increase the affinity of IFIH1 for RNA, leading to immune upregulation and inflammatory disease. 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.