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

    Research output: Contribution to journalArticlepeer-review


    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.
    Original languageEnglish
    JournalAmerican Journal of Human Genetics
    Issue number2
    Publication statusPublished - 5 Feb 2015


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