Genetic and phenotypic spectrum associated with IFIH1 gain-of-function
Rice, Gillian I. (University of Manchester)
Park, Sehoon (Boston Children's Hospital (Boston, Estats Units d'Amèrica))
Gavazzi, Francesco (Children's Hospital of Philadelphia (Pennsilvània))
Adang, Laura A. (Children's Hospital of Philadelphia (Pennsilvània))
Ayuk, Loveline A. (Dumfries and Galloway Royal Infirmary)
Eyck, Lien Van (Institut Imagine (Paris, França))
Seabra, Luis (Institut Imagine (Paris, França))
Barrea, Christophe (Université de Liège)
Battini, Roberta (IRCCS Fondazione Stella Maris)
Belot, Alexandre (Université de Lyon)
Berg, Stefan (The Queen Silvia Children's Hospital)
de Villemeur, Thierry Billette (Sorbonne Université)
Bley, Annette E. (University Children's Hospital)
Blumkin, Lubov (Tel-Aviv University)
Boespflug-Tanguy, Odile (Centre de Référence Maladies Rares "Leucodystrophies")
Briggs, Tracy A. (St Mary's Hospital)
Brimble, Elise (Stanford University School of Medicine)
Dale, Russell C.. (University of Sydney)
Darin, Niklas (The Queen Silvia Children's Hospital)
Debray, François-Guillaume (Université de Liège)
De Giorgis, Valentina (IRCCS Mondino Foundation)
Denecke, Jonas (University Medical Center Hamburg Eppendorf)
Doummar, Diane (Hôpital Armand Trousseau (París, França))
Hagelsrum, Gunilla Drake af (PeThe Queen Silvia Children's Hospital)
Eleftheriou, Despina (University College London (UCL))
Estienne, Margherita (Istituto Neurologico Carlo Besta)
Fazzi, Elisa (University of Brescia. Department of Experimental and Clinical Sciences)
Feillet, François (Centre de Référence des maladies métaboliques de Nancy (França))
Galli, Jessica (University of Brescia. Department of Experimental and Clinical Sciences)
Hartog, Nicholas (Michigan State University College of Human Medicine)
Harvengt, Julie (University of Liège. Department of Medical Genetics)
Heron, Bénédicte (Hôpital Trousseau (París, França). Centre Référence des Maladies Lysosomales)
Heron, Delphine (Groupe Hospitalier Pitié-Salpêtrière (París, França). UF Génétique Médicale et Centre de Référence "Déficiences Intellectuelles)
Kelly, Diedre A. (Birmingham Women's and Children's Hospital (Regne Unit))
Lev, Dorit (The Rina Mor Institute of Medical Genetics (Holon, Israel))
Levrat, Virginie (Centre Hospitalier Annecy Genevois (Pringy, França))
Livingston, John H. (Leeds General Infirmary (Leeds, Regne Unit))
Marti, Itxaso (Hospital Universitario de Donostia (Sant Sebastià, País Basc))
Mignot, Cyril (GH Pitié-Sapêtrière (París, França). Departement de Génétique & Centre de Référence Déficience Intellectuelle de cause rare)
Mochel, Fanny (Sorbonne Universités. Institut du Cerveau et de la Moelle épinière)
Nougues, Marie-Christine (Hôpital Armand Trousseau (París, França))
Oppermann, Ilena (University Medical Center Hamburg Eppendorf)
Pérez-Dueñas, Belén (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Popp, Bernt (Friedrich-Alexander-Universität Erlangen-Nürnberg. Institute of Human Genetics)
Rodero, Mathieu P. (Institut Imagine (París, França). Laboratory of Neurogenetics and Neuroinflammation)
Rodriguez, Diana (Hôpital Trousseau (París, França). Centre Référence des Maladies Lysosomales)
Saletti, Veronica (Fondazione IRCCS Istituto Neurologico Carlo Besta (Milà, Itàlia))
Sharpe, Cia (Starship Children's Hospital (Auckland, Nova Zelanda))
Tonduti, Davide (V. Buzzi Children's Hospital (Milà, Itàlia))
Vadlamani, Gayatri (Leeds General Infirmary (Leeds, Regne Unit))
Haren, Keith Van (Stanford University School of Medicine. Department of Neurology)
Vila, Miguel Tomas (Hospital Universitari i Politècnic La Fe (València))
Vogt, Julie (West Midlands Regional Clinical Genetics Service (Regne Unit))
Wassmer, Evangeline (Birmingham Women's and Children's Hospital (Regne Unit))
Wiedemann, Arnaud (Centre de Référence des maladies métaboliques de Nancy (França))
Wilson, Callum J. (Starship Children's Hospital (Auckland, Nova Zelanda))
Zerem, Ayelet (Tel-Aviv Universitym. Sackler Faculty of Medicine)
Zweier, Christiane (Friedrich-Alexander-Universität Erlangen-Nürnberg)
Zuberi, Sameer M. (University of Glasgow. School of Medicine)
Orcesi, Simona (University of Pavia. Department of Brain and Behavioural Sciences)
Vanderver, Adeline L. (Children's Hospital of Philadelphia (Pennsilvània))
Hur, Sun (Boston Children's Hospital (Boston, Estats Units d'Amèrica))
Crow, Yanick J. (University of Edinburgh. Institute of Genetics and Molecular Medicine)
Universitat Autònoma de Barcelona

Date:	2020
Abstract:	IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13. 5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Aicardi-Goutières syndrome ; IFIH1 ; MDA5 ; Singleton Merten syndrome ; Type I interferonopathy
Published in:	Human mutation, Vol. 41 (january 2020) , p. 837-849, ISSN 1098-1004

DOI: 10.1002/humu.23975
PMID: 31898846

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