Singleton-Merten Syndrome: a rare autoimmune disorder caused by a specific IFIH1 mutation.

s of the 51st Workshop for Pediatric Research 51st Workshop for Pediatric Research Gottingen, Germany 16-17 April 2015 This supplement has not been sponsored. Meeting abstracts Meeting abstract Singleton-Merten Syndrome(SMS) is a rare autosomal-dominant disorder characterized by a variety of symptoms including extreme calcifications of the ascending aortaand cardiac valves, dental anomalies(early onset periodontitis, root resorption), psoriasis and widened medullary cavitiesof the phalangeswith focal osteoporosis. Employing whole exome sequencingof five SMS individuals of three families we identified the missense mutation, c.2465G>A (p.Arg822Gln) in the interferon induced with helicase C domain 1 (IFIH1) gene. Additional Sanger sequencingconfirmed co-segregation of the mutation with the disorder. IFIH1, encoding melanoma differentiation-associatedprotein 5 ( MDA5), is a member of the RIG-I-like receptorfamily and functions as a cytoplasmic pattern recognition receptorrecognizing viral double stranded RNA (dsRNA). Immunohistochemistry demonstrated the localization of MDA5in all affected target tissues including heart, skin and cartilage. Functional analysis revealed that the IFIH1 c.2465G>A mutation enhanced MDA5function in interferon beta induction after polyinosinic:polycytidylic acid(poly (I:C)) stimulation in vitro. This indicates that SMS- MDA5is hyperactive to non-self dsRNA. According to additional in vitro studies, interferon signature genes including SIGLEC1 were upregulated in blood and dental cells derived from SMS individuals. Taken together, our data demonstrate that the MDA5gain-of-function mutation p.Arg822Gln causes the autosomal dominant disorder SMS through dysregulation of the human innate immune response.