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Title: Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling
Authors: 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
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 #
Issue Date: May-2014
Publisher: Nature Publishing Group
Series Title: Nature Genetics vol:46 issue:5 pages:503-9
Article number: 10.1038/ng.2933
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 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.
ISSN: 1061-4036
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Development and Regeneration, Campus Kulak Kortrijk
Organ Systems (+)
× corresponding author
# (joint) last author

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