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

Autor:	Catherine Vanhulle, Lynne A. Wolfe, Chumei Li, Eileen Baildam, Bertrand Isidor, John Tolmie, Yoandris del Toro Duany, Yanick J. Crow, Gabriella M A Forte, Gillian I. Rice, Simona Orcesi, Mondher Chouchane, Michael W. Beresford, Nuno Cordeiro, Beverley Anderson, Liesbeth De Waele, Pierre Lebon, Diana Rodriguez, James O'Sullivan, Marta Szybowska, Rolando Cimaz, Isabelle Desguerre, Giada Ariaudo, Manoj P. Menezes, Kate Webb, Robyn Whitney, Sun Hur, Simon G. Williams, Joyce Davidson, Russell C. Dale, Andrew Latchman, Laurence Faivre, Abigail Collins, Robert Robinson, Adeline Vanderver, Christiaan Scott, Iain B. McInnes, Enrica Riva, Cyril Mignot, Roberta Battini, José Pedro Vieira, Brigitte Bader-Meunier, Emma M. Jenkinson, Elisa Fazzi, Paolo Picco, Lieven Lagae, Elisabetta Salvatici, Manuela Casarano, Sameer M. Zuberi, Charles Marques Lourenço, Maria Margherita Mancardi, Alice Masurel-Paulet, John H. Livingston
Rok vydání:	2014
Předmět:	Models Molecular Interferon-Induced Helicase IFIH1 Molecular Sequence Data HDE NEU PED Electrophoretic Mobility Shift Assay Biology medicine.disease_cause Nervous System Malformations Real-Time Polymerase Chain Reaction Article DEAD-box RNA Helicases Immune system Autoimmune Diseases of the Nervous System Downregulation and upregulation Analysis of Variance Base Sequence Exome HEK293 Cells Humans Interferon Type I Microsatellite Repeats Mutation Sequence Analysis DNA Signal Transduction Spectrum Analysis Phenotype Genetics Models Interferon medicine Molecular RNA MDA5 DNA Molecular biology 3. Good health Interferon Tipo I Cancer research Signal transduction Sequence Analysis Interferon type I medicine.drug
Zdroj:	Nature Genetics; Vol 46 Nature Genetics Nature genetics Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) Agência para a Sociedade do Conhecimento (UMIC)-FCT-Sociedade da Informação instacron:RCAAP
ISSN:	1546-1718
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9d0ab15ef0ea89e7de71b0fd808541bf https://pubmed.ncbi.nlm.nih.gov/25080300 Zobrazit plný text záznamu Plný text ve formátu PDF