Title |
Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling
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Published in |
Nature Genetics, March 2014
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DOI | 10.1038/ng.2933 |
Pubmed ID | |
Authors |
Gillian I Rice, Yoandris del Toro Duany, Emma M Jenkinson, Gabriella M A Forte, Beverley H Anderson, Giada Ariaudo, Brigitte Bader-Meunier, Eileen M Baildam, Roberta Battini, Michael W Beresford, Manuela Casarano, Mondher Chouchane, Rolando Cimaz, Abigail E Collins, Nuno J V Cordeiro, Russell C Dale, Joyce E Davidson, Liesbeth De Waele, Isabelle Desguerre, Laurence Faivre, Elisa Fazzi, Bertrand Isidor, Lieven Lagae, Andrew R Latchman, Pierre Lebon, Chumei Li, John H Livingston, Charles M Lourenço, Maria Margherita Mancardi, Alice Masurel-Paulet, Iain B McInnes, Manoj P Menezes, Cyril Mignot, James O'Sullivan, Simona Orcesi, Paolo P Picco, Enrica Riva, Robert A Robinson, Diana Rodriguez, Elisabetta Salvatici, Christiaan Scott, Marta Szybowska, John L Tolmie, Adeline Vanderver, Catherine Vanhulle, Jose Pedro Vieira, Kate Webb, Robyn N Whitney, Simon G Williams, Lynne A Wolfe, Sameer M Zuberi, Sun Hur, Yanick J Crow |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
New Zealand | 1 | 14% |
Israel | 1 | 14% |
France | 1 | 14% |
Unknown | 4 | 57% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Scientists | 5 | 71% |
Members of the public | 2 | 29% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 5 | 1% |
Spain | 1 | <1% |
France | 1 | <1% |
Germany | 1 | <1% |
Unknown | 388 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 79 | 20% |
Student > Ph. D. Student | 70 | 18% |
Student > Bachelor | 35 | 9% |
Student > Master | 32 | 8% |
Student > Doctoral Student | 27 | 7% |
Other | 72 | 18% |
Unknown | 81 | 20% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 83 | 21% |
Agricultural and Biological Sciences | 79 | 20% |
Medicine and Dentistry | 67 | 17% |
Immunology and Microbiology | 47 | 12% |
Neuroscience | 10 | 3% |
Other | 20 | 5% |
Unknown | 90 | 23% |