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. Epub 2015 Jan 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Aortic Diseases / genetics*
  • Arteries / pathology
  • Base Sequence
  • Calcinosis / genetics
  • Calcinosis / pathology
  • DEAD-box RNA Helicases / chemistry
  • DEAD-box RNA Helicases / genetics*
  • DEAD-box RNA Helicases / 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
  • Tooth Abnormalities / pathology
  • Vascular Calcification / genetics*


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

Supplementary concepts

  • Singleton Merten syndrome