Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Rutsch, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED MacDougall, Mary UNSPECIFIED UNSPECIFIED UNSPECIFIED Lu, Changming UNSPECIFIED UNSPECIFIED UNSPECIFIED Buers, Insa UNSPECIFIED UNSPECIFIED UNSPECIFIED Mamaeva, Olga UNSPECIFIED UNSPECIFIED UNSPECIFIED Nitschke, Yvonne UNSPECIFIED UNSPECIFIED UNSPECIFIED Rice, Gillian I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Erlandsen, Heidi UNSPECIFIED UNSPECIFIED UNSPECIFIED Kehl, Hans Gerd UNSPECIFIED orcid.org/0000-0002-6555-8174 UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoehne, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Crow, Yanick J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Feigenbaum, Annette UNSPECIFIED UNSPECIFIED UNSPECIFIED Hennekam, Raoul C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-407769
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:	Keywords Language GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CHINESE POPULATION; RNA HELICASES; PSORIASIS; RESPONSES; VIRUSES; MOTIFS; MDA5 Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40776