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Recessive TTN truncating mutations define novel forms of core myopathy with heart disease

Item Type:Article
Title:Recessive TTN truncating mutations define novel forms of core myopathy with heart disease
Creators Name:Chauveau, C. and Bonnemann, C.G. and Julien, C. and Kho, A.L. and Marks, H. and Talim, B. and Maury, P. and Arne-Bes, M.C. and Uro-Coste, E. and Alexandrovich, A. and Vihola, A. and Schafer, S. and Kaufmann, B. and Medne, L. and Hübner, N. and Foley, A.R. and Santi, M. and Udd, B. and Topaloglu, H. and Moore, S.A. and Gotthardt, M. and Samuels, M.E. and Gautel, M. and Ferreiro, A.
Abstract:Core myopathies (CM), the main non-dystrophic myopathy in childhood, remain genetically unexplained in many cases. Heart disease is not considered part of the typical CM spectrum. No congenital heart defect has been reported, and childhood-onset cardiomyopathy has been documented in only two CM families with homozygous mutations of the TTN gene. TTN encodes titin, a giant protein of striated muscles. Recently, heterozygous TTN truncating mutations have also been reported as a major cause of dominant dilated cardiomyopathy. However, relatively few TTN mutations and phenotypes are known, and titin pathophysiological role in cardiac and skeletal muscle conditions is incompletely understood.We analyzed a series of 23 families with congenital CM and primary heart disease using TTN M-line targeted sequencing followed in selected patients by whole-exome sequencing and functional studies. We identified 7 novel homozygous or compound-heterozygous TTN mutations (5 in the M-line, 5 truncating) in 17% patients. Heterozygous parents were healthy. Phenotype analysis identified four novel titinopathies, including cardiac septal defects, left ventricular non-compaction, Emery-Dreifuss muscular dystrophy or arthrogryposis. Additionally, in vitro studies documented the first-reported absence of the titin kinase domain in humans, leading to a severe antenatal phenotype. We establish that CM are associated with a large range of heart conditions of which TTN mutations are a major cause, thereby expanding TTN mutational and phenotypic spectrum. Additionally, our results suggest titin kinase implication in cardiac morphogenesis and demonstrate that heterozygous TTN truncating mutations may not manifest unless associated with a second mutation, reassessing the paradigm of their dominant expression.
Keywords:Central Core Myopathy, Connectin, Consanguinity, Genetic Association Studies, Genetic Predisposition to Disease, Heart Diseases, Heterozygote, Nonsense Codon, Pedigree, Phenotype, Recessive Genes, Skeletal Muscle
Source:Human Molecular Genetics
Publisher:Oxford University Press
Page Range:980-991
Date:15 February 2014
Official Publication:https://doi.org/10.1093/hmg/ddt494
PubMed:View item in PubMed

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