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

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.

• Authors: 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
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 96 Issue 2 Pg. 275-82 (Feb 05 2015) ISSN: 1537-6605 [Electronic] United States
• PMID: 25620204 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Interferon-beta
• IFIH1 protein, human
• DEAD-box RNA Helicases
• Interferon-Induced Helicase, IFIH1

Topics

• Amino Acid Sequence
• Aortic Diseases (genetics)
• Arteries (pathology)
• Base Sequence
• Calcinosis (genetics, pathology)
• DEAD-box RNA Helicases (chemistry, genetics, metabolism)
• Dental Enamel Hypoplasia (genetics)
• Exome (genetics)
• Genes, Dominant (genetics)
• Humans
• Immunohistochemistry
• Interferon-Induced Helicase, IFIH1
• Interferon-beta (metabolism)
• Metacarpus (abnormalities)
• Models, Molecular
• Molecular Sequence Data
• Muscular Diseases (genetics)
• Mutation, Missense (genetics)
• Odontodysplasia (genetics)
• Osteoporosis (genetics)
• Pedigree
• Phenotype
• Sequence Analysis, DNA
• Tooth Abnormalities (genetics, pathology)
• Vascular Calcification (genetics)