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Am J Hum Genet. 2015 Feb 5;96(2):275-82. doi: 10.1016/j.ajhg.2014.12.014. Epub 2015 Jan 22.

A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome.

Author information

1
Department of General Pediatrics, Muenster University Children's Hospital, 48149 Muenster, Germany. Electronic address: rutschf@ukmuenster.de.
2
Institute of Oral Health Research, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: macdougall@uab.edu.
3
Institute of Oral Health Research, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
4
Department of General Pediatrics, Muenster University Children's Hospital, 48149 Muenster, Germany.
5
Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester M13 9PT, UK.
6
Department of Pediatric Cardiology, Muenster University Children's Hospital, 48149 Muenster, Germany.
7
Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
8
Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
9
Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester M13 9PT, UK; INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris 75015, France; Paris Descartes - Sorbonne Paris Cité University, Institute Imagine, Paris 75006, France.
10
Division of Clinical and Metabolic Genetics, Hospital for Sick Children, University of San Diego, San Diego, CA 92123, USA.
11
Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.

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-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.

PMID:
25620204
PMCID:
PMC4320263
DOI:
10.1016/j.ajhg.2014.12.014
[Indexed for MEDLINE]
Free PMC Article

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