Rutsch, Frank, MacDougall, Mary, Lu, Changming, Buers, Insa, Mamaeva, Olga, Nitschke, Yvonne, Rice, Gillian I., Erlandsen, Heidi, Kehl, Hans Gerd ORCID: 0000-0002-6555-8174, Thiele, Holger, Nuernberg, Peter, Hoehne, Wolfgang, Crow, Yanick J., Feigenbaum, Annette and Hennekam, Raoul C. (2015). A Specific IFIH1 Gain-of-Function Mutation Causes Singleton-Merten Syndrome. Am. J. Hum. Genet., 96 (2). S. 275 - 283. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rutsch, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
MacDougall, MaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lu, ChangmingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buers, InsaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mamaeva, OlgaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nitschke, YvonneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rice, Gillian I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erlandsen, HeidiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kehl, Hans GerdUNSPECIFIEDorcid.org/0000-0002-6555-8174UNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoehne, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Crow, Yanick J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Feigenbaum, AnnetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hennekam, Raoul C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-412654
DOI: 10.1016/j.ajhg.2014.12.014
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 96
Number: 2
Page Range: S. 275 - 283
Date: 2015
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CHINESE POPULATION; RNA HELICASES; PSORIASIS; RESPONSES; VIRUSES; MOTIFS; MDA5Multiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/41265

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