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

Claire Chauveau, Carsten G. Bonnemann, Cedric Julien, Ay Lin Kho, Harold Marks, Beril Talim, Philippe Maury, Marie Christine Arne-Bes, Emmanuelle Uro-Coste, Alexander Alexandrovich, Anna Vihola, Sebastian Schafer, Beth Kaufmann, Livija Medne, Norbert Huebner, A. Reghan Foley, Mariarita Santi, Bjarne Udd, Haluk Topaloglu, Steven A. MooreMichael Gotthardt, Mark E. Samuels, Mathias Gautel, Ana Ferreiro*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

141 Citations (Scopus)

Abstract

Core myopathies (CM), the main non-dystrophic myopathies 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 seven novel homozygous or compound heterozygous TTN mutations (five in the M-line, five truncating) in 17 patients. Heterozygous parents were healthy. Phenotype analysis identified four novel titinopathies, including cardiac septal defects, left ventricular non-compaction, EmeryDreifuss muscular dystrophy or arthrogryposis. Additionally, in vitro studies documented the first-reported absence of a functional 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 the 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.

Original languageEnglish
Pages (from-to)980-991
Number of pages12
JournalHuman Molecular Genetics
Volume23
Issue number4
DOIs
Publication statusPublished - 15 Feb 2014

Keywords

  • TIBIAL MUSCULAR-DYSTROPHY
  • EARLY RESPIRATORY-FAILURE
  • MULTI-MINICORE DISEASE
  • C-TERMINAL TITIN
  • DILATED CARDIOMYOPATHY
  • HYPERTROPHIC CARDIOMYOPATHY
  • CONGENITAL MYOPATHY
  • HEREDITARY MYOPATHY
  • IMMUNOELECTRON MICROSCOPY
  • CARDIAC INVOLVEMENT

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