IFIH1 /MDA5 Mutation Causes Singleton-Merten Syndrome: An Innate Immune Disorder

Singleton-Merten Syndrome (SMS; MIM 182250) is a rare autosomal-dominant disorder characterized by heart calcifications causing premature death with psoriasis, widened phalanges medullary cavities, focal osteoporosis, delayed tooth eruption, short roots, rapid periodontisis and early loss of teeth through complete root resorption. Objective: To determine the SMS disease causing gene. Methods: 1)Perform whole exome sequencing on four SMS patients/three families; 2)determine structural signficance of mutation; 3)characterize the identified gene expression in affected tissues (qRT-PCR and immunohistochemsitry-IHC); and 4) analyze Affymetrix GeneChip expression profiles of SMS versus control dental cell populations. Results: A missense IFIH1mutation segregated with SMS was identified not present in the Single Nucleotide Polymorphism or the 1000 Genomes databases. IFIH1, located on  2q24.2  with 17 exons, encodes  melanoma differentiation associated protein 5 (MDA5) a member of the RIG-I-like receptor family. MDA5 regulates innate inflammatory signals for cytoplasmic double-stranded RNA and initiates antiviral responses by producing type I and type II interferons. The p.R822Q MDA5 mutation is at a highly conserved amino acid in the helicase domain. Structural analysis revealed a positive surface potential for RNA orientation during unwinding that is changed, altering  affinity and/or activity of the helicase. MDA5 expression was shown in heart tissue, skin, alveolar bone and tooth ameloblasts, odontoblasts  and the periodontal apparatus; all disease targeted tissues. Ingenuity pathway analysis of  dental SMS versus control cell expression profiles revealed inflammatory response/immunity networks and interferon and type I diabetes mellitus signalling pathways were the most significantly dysregulated. Genome-wide association studies have linked MDA5-SNPs with type I diabetes and psoriasis. Conclusions:  The p.R822Q MDA5 mutation has  a causative role in SMS based on the common mutation in 3 families (one sporatic), protein structural changes, tissue localization and alteration of mineralization and inflammatory networks. Our study suggests for the first time that SMS is a innate immune disease.