Journal article
Recessive TTN truncating mutations define novel forms of core myopathy with heart disease
Human molecular genetics, Vol.23(4), pp.980-991
02/15/2014
DOI: 10.1093/hmg/ddt494
PMCID: PMC3954110
PMID: 24105469
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, Emery–Dreifuss 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.
Details
- Title: Subtitle
- Recessive TTN truncating mutations define novel forms of core myopathy with heart disease
- Creators
- Claire Chauveau - Groupe Hospitalier Pitié-SalpêtrièreCarsten G Bonnemann - National Institutes of HealthCedric Julien - Groupe Hospitalier Pitié-SalpêtrièreAy Lin Kho - King's College London, BHF Centre of Research ExcellenceHarold Marks - The Center for Neurological and Neurodevelopmental HealthBeril Talim - Hacettepe UniversityPhilippe Maury - CHU Rangueil and INSERM UMR 1037Marie Christine Arne-Bes - CHU Rangueil and INSERM UMR 1037Emmanuelle Uro-Coste - CHU Rangueil and INSERM UMR 1037Alexander Alexandrovich - King's College London, BHF Centre of Research ExcellenceAnna Vihola - University of HelsinkiSebastian Schafer - ,Beth Kaufmann - ,Livija Medne - ,Norbert Hübner - ,A. Reghan FoleyMariarita Santi - The Children's Hospital of Philadelphia, University of PennsylvaniaBjarne Udd - University of HelsinkiHaluk Topaloglu - Hacettepe UniversitySteven A Moore - The University of IowaMichael Gotthardt - Max Delbrück Center for Molecular MedicineMark E Samuels - Université de MontréalMathias Gautel - King's College London, BHF Centre of Research ExcellenceAna Ferreiro - Groupe Hospitalier Pitié-Salpêtrière
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.23(4), pp.980-991
- Publisher
- Oxford University Press
- DOI
- 10.1093/hmg/ddt494
- PMID
- 24105469
- PMCID
- PMC3954110
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Language
- English
- Date published
- 02/15/2014
- Academic Unit
- Pathology
- Record Identifier
- 9984046929202771
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