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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type i interferon signaling
Nature Genetics, Volume 46, No. 5, Year 2014
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Description
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. © 2014 Nature America, Inc. All rights reserved.
Authors & Co-Authors
Rice, Gillian I.
Unknown Affiliation
Del Toro Duany, Yoandris
Unknown Affiliation
Jenkinson, Emma M.
Unknown Affiliation
Forte, Gabriella M.A.
Unknown Affiliation
Anderson, Beverley H.
Unknown Affiliation
Ariaudo, Giada
Unknown Affiliation
Bader-Meunier, Brigitte
Unknown Affiliation
Baildam, Eileen M.
Unknown Affiliation
Battini, Roberta
Unknown Affiliation
Beresford, Michael William
Unknown Affiliation
Casarano, Manuela
Unknown Affiliation
Chouchane, Mondher
Unknown Affiliation
Cimaz, Rolando G.
Unknown Affiliation
Collins, Abigail E.
Unknown Affiliation
Cordeiro, Nuno J.V.
Unknown Affiliation
Dale, Russell C.
Unknown Affiliation
Davidson, Joyce E.
Unknown Affiliation
de Waele, Liesbeth M.H.
Unknown Affiliation
Desguerre, Isabelle
Unknown Affiliation
Faivre, Laurence Olivier
Unknown Affiliation
Fazzi, Elisa Maria
Unknown Affiliation
Isidor, Bertrand
Unknown Affiliation
Lagae, Lieven G.
Unknown Affiliation
Latchman, Andrew R.
Unknown Affiliation
Lebon, Pierre
Unknown Affiliation
Li, Chumei
Unknown Affiliation
Livingston, John H.
Unknown Affiliation
Lourenc¸o, Charles Marques
Unknown Affiliation
Mancardi, Maria Margherita
Unknown Affiliation
Masurel-Paulet, Alice
Unknown Affiliation
McInnes, Iain B.
Unknown Affiliation
Menezes, Manoj P.
Unknown Affiliation
Mignot, Cyril
Unknown Affiliation
O'Sullivan, James
Unknown Affiliation
Orcesi, Simona
Unknown Affiliation
Picco, Paolo
Unknown Affiliation
Riva, Enrica
Unknown Affiliation
Robinson, Robert A.
Unknown Affiliation
Rodriguez, Diana P.
Unknown Affiliation
Salvatici, Elisabetta
Unknown Affiliation
Scott, Christiaan
Unknown Affiliation
Szybowska, Marta
Unknown Affiliation
Tolmie, J. L.
Unknown Affiliation
Vanderver, Adeline L.
Unknown Affiliation
Vanhulle, Catherine
Unknown Affiliation
Vieira, Jose P.
Unknown Affiliation
Webb, Kate
Unknown Affiliation
Whitney, Robyn N.
Unknown Affiliation
Williams, Simon G.
Unknown Affiliation
Wolfe, Lynne A.
Unknown Affiliation
Zuberi, Sameer M.
Unknown Affiliation
Hur, Sun
Unknown Affiliation
Yanick J. Crow, Yanick
Unknown Affiliation
Statistics
Citations: 494
Authors: 53
Affiliations: 39
Identifiers
Doi:
10.1038/ng.2933
ISSN:
10614036
e-ISSN:
15461718
Research Areas
Genetics And Genomics