A Specific IFIH1 Gain-of-Function Mutation Causes Singleton-Merten Syndrome

• Published in: American journal of human genetics Vol. 96; no. 2; pp. 275 - 282
• Main Authors: Rutsch, Frank, MacDougall, Mary, Lu, Changming, Buers, Insa, Mamaeva, Olga, Nitschke, Yvonne, Rice, Gillian I., Erlandsen, Heidi, Kehl, Hans Gerd, Thiele, Holger, Nürnberg, Peter, Höhne, Wolfgang, Crow, Yanick J., Feigenbaum, Annette, Hennekam, Raoul C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.02.2015; Cell Press; Elsevier
• Subjects: Amino Acid Sequence; Aortic Diseases - genetics; Arteries - pathology; Autoimmune diseases; Base Sequence; Calcinosis - genetics; Calcinosis - pathology; DEAD-box RNA Helicases - chemistry; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Dental Enamel Hypoplasia - genetics; Exome - genetics; Genes, Dominant - genetics; Genetic disorders; Genomics; Humans; Immunohistochemistry; Interferon; Interferon-beta - metabolism; Interferon-Induced Helicase, IFIH1; Metacarpus - abnormalities; Models, Molecular; Molecular Sequence Data; Muscular Diseases - genetics; Mutation; Mutation, Missense - genetics; Odontodysplasia - genetics; Osteoporosis - genetics; Pedigree; Phenotype; Sequence Analysis, DNA; Tooth Abnormalities - genetics; Tooth Abnormalities - pathology; Vascular Calcification - genetics
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2014.12.014

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.