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. Moore; Michael Gotthardt; Mark E. Samuels; Mathias Gautel; Ana Ferreiro

doi:10.1093/hmg/ddt494

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 journal › Article › peer-review

148 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 language	English
Pages (from-to)	980-991
Number of pages	12
Journal	Human Molecular Genetics
Volume	23
Issue number	4
DOIs	https://doi.org/10.1093/hmg/ddt494
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/hmg/ddt494

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Chauveau, C., Bonnemann, C. G., Julien, C., Kho, A. L., Marks, H., Talim, B., Maury, P., Arne-Bes, M. C., Uro-Coste, E., Alexandrovich, A., Vihola, A., Schafer, S., Kaufmann, B., Medne, L., Huebner, N., Foley, A. R., Santi, M., Udd, B., Topaloglu, H., ... Ferreiro, A. (2014). Recessive TTN truncating mutations define novel forms of core myopathy with heart disease. Human Molecular Genetics, 23(4), 980-991. https://doi.org/10.1093/hmg/ddt494

@article{02f08636d816465a8b96eac4ebb6af27,

title = "Recessive TTN truncating mutations define novel forms of core myopathy with heart disease",

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.",

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",

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

year = "2014",

month = feb,

day = "15",

doi = "10.1093/hmg/ddt494",

language = "English",

volume = "23",

pages = "980--991",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "4",

}

Chauveau, C, Bonnemann, CG, Julien, C, Kho, AL, Marks, H, Talim, B, Maury, P, Arne-Bes, MC, Uro-Coste, E, Alexandrovich, A, Vihola, A, Schafer, S, Kaufmann, B, Medne, L, Huebner, N, Foley, AR, Santi, M, Udd, B, Topaloglu, H, Moore, SA, Gotthardt, M, Samuels, ME, Gautel, M & Ferreiro, A 2014, 'Recessive TTN truncating mutations define novel forms of core myopathy with heart disease', Human Molecular Genetics, vol. 23, no. 4, pp. 980-991. https://doi.org/10.1093/hmg/ddt494

TY - JOUR

T1 - Recessive TTN truncating mutations define novel forms of core myopathy with heart disease

AU - Chauveau, Claire

AU - Bonnemann, Carsten G.

AU - Julien, Cedric

AU - Kho, Ay Lin

AU - Marks, Harold

AU - Talim, Beril

AU - Maury, Philippe

AU - Arne-Bes, Marie Christine

AU - Uro-Coste, Emmanuelle

AU - Alexandrovich, Alexander

AU - Vihola, Anna

AU - Schafer, Sebastian

AU - Kaufmann, Beth

AU - Medne, Livija

AU - Huebner, Norbert

AU - Foley, A. Reghan

AU - Santi, Mariarita

AU - Udd, Bjarne

AU - Topaloglu, Haluk

AU - Moore, Steven A.

AU - Gotthardt, Michael

AU - Samuels, Mark E.

AU - Gautel, Mathias

AU - Ferreiro, Ana

PY - 2014/2/15

Y1 - 2014/2/15

N2 - 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.

AB - 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.

KW - TIBIAL MUSCULAR-DYSTROPHY

KW - EARLY RESPIRATORY-FAILURE

KW - MULTI-MINICORE DISEASE

KW - C-TERMINAL TITIN

KW - DILATED CARDIOMYOPATHY

KW - HYPERTROPHIC CARDIOMYOPATHY

KW - CONGENITAL MYOPATHY

KW - HEREDITARY MYOPATHY

KW - IMMUNOELECTRON MICROSCOPY

KW - CARDIAC INVOLVEMENT

U2 - 10.1093/hmg/ddt494

DO - 10.1093/hmg/ddt494

M3 - Article

SN - 0964-6906

VL - 23

SP - 980

EP - 991

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 4

ER -

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

Abstract

Keywords

UN SDGs

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