title: A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome.
abstract: Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis. To determine the molecular etiology of this disease, we performed whole-exome sequencing and targeted Sanger sequencing. We identified a common missense mutation, c.2465G>A (p.Arg822Gln), in interferon induced with helicase C domain 1 (IFIH1, encoding melanoma differentiation-associated protein 5 [MDA5]) in four SMS subjects from two families and a simplex case. IFIH1 has been linked to a number of autoimmune disorders, including Aicardi-Goutières syndrome. Immunohistochemistry demonstrated the localization of MDA5 in all affected target tissues. In vitro functional analysis revealed that the IFIH1 c.2465G>A mutation enhanced MDA5 function in interferon beta induction. Interferon signature genes were upregulated in SMS individuals' blood and dental cells. Our data identify a gain-of-function IFIH1 mutation as causing SMS and leading to early arterial calcification and dental inflammation and resorption.
authors.affiliation: Department of General Pediatrics, Muenster University Children's Hospital, 48149 Muenster, Germany. Electronic address: rutschf@ukmuenster.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Rutsch
authors.affiliation: Institute of Oral Health Research, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: macdougall@uab.edu.
authors.forename: Mary
authors.initials: M
authors.lastname: MacDougall
authors.affiliation: Institute of Oral Health Research, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Changming
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of General Pediatrics, Muenster University Children's Hospital, 48149 Muenster, Germany.
authors.forename: Insa
authors.initials: I
authors.lastname: Buers
authors.affiliation: Institute of Oral Health Research, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Mamaeva
authors.affiliation: Department of General Pediatrics, Muenster University Children's Hospital, 48149 Muenster, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Nitschke
authors.affiliation: Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester M13 9PT, UK.
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Rice
authors.affiliation: Institute of Oral Health Research, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Erlandsen
authors.affiliation: Department of Pediatric Cardiology, Muenster University Children's Hospital, 48149 Muenster, Germany.
authors.forename: Hans Gerd
authors.initials: HG
authors.lastname: Kehl
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Höhne
authors.affiliation: Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester M13 9PT, UK; INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris 75015, France; Paris Descartes - Sorbonne Paris Cité University, Institute Imagine, Paris 75006, France.
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
authors.affiliation: Division of Clinical and Metabolic Genetics, Hospital for Sick Children, University of San Diego, San Diego, CA 92123, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Feigenbaum
authors.affiliation: Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Raoul C
authors.initials: RC
authors.lastname: Hennekam
mesh_terms: D000595:Amino Acid Sequence; D001018:Aortic Diseases / Q000235:genetics*; D001158:Arteries / Q000473:pathology; D001483:Base Sequence; D002114:Calcinosis / Q000235:genetics / Q000473:pathology; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D003744:Dental Enamel Hypoplasia / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000378:metabolism; D008663:Metacarpus / Q000002:abnormalities*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D018126:Odontodysplasia / Q000235:genetics*; D010024:Osteoporosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D014071:Tooth Abnormalities / Q000235:genetics / Q000473:pathology; D061205:Vascular Calcification / Q000235:genetics*
chemical_list: D016899:Interferon-beta; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1