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

Frank Rutsch, Mary Macdougall, Changming Lu, Insa Buers, Olga Mamaeva, Yvonne Nitschke, Gillian I. Rice, Heidi Erlandsen, Hans Gerd Kehl, Holger Thiele, Peter Nürnberg, Wolfgang Höhne, Yanick J. Crow, Annette Feigenbaum, Raoul C. Hennekam

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164 Citations (Scopus)

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-Goutieres 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
Original languageEnglish
Pages (from-to)275-282
JournalAmerican journal of human genetics
Volume96
Issue number2
DOIs
Publication statusPublished - 2015

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