A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome
- Am J Hum Genet. 2015 Feb 5;96(2):275-82. doi: 10.1016/j.ajhg.2014.12.014.
- 1. Department of General Pediatrics, Muenster University Children's Hospital, 48149 Muenster, Germany. Electronic address: [email protected].
- 2. Institute of Oral Health Research, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: [email protected].
- 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.
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.