C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy

Virginie Carmignac; Mustafa A M Salih; Susana Quijano-Roy; Sylvie Marchand; Molham M Al Rayess; Maowia M Mukhtar; Jon A Urtizberea; Siegfried Labeit; Pascale Guicheney; France Leturcq; Mathias Gautel; Michel Fardeau; Kevin P Campbell; Isabelle Richard; Brigitte Estournet; Ana Ferreiro

doi:10.1002/ana.21089

C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy

Virginie Carmignac, Mustafa A M Salih, Susana Quijano-Roy, Sylvie Marchand, Molham M Al Rayess, Maowia M Mukhtar, Jon A Urtizberea, Siegfried Labeit, Pascale Guicheney, France Leturcq, Mathias Gautel, Michel Fardeau, Kevin P Campbell, Isabelle Richard, Brigitte Estournet, Ana Ferreiro

Research output: Contribution to journal › Article › peer-review

199 Citations (Scopus)

Abstract

OBJECTIVE: The giant protein titin is essential for striated muscle development, structure, and elasticity. All titin mutations reported to date cause late-onset, dominant disorders involving either skeletal muscle or the heart. Our aim was to delineate the phenotype and determine the genetic defects in two consanguineous families with an early-onset, recessive muscle and cardiac disorder.

METHODS: Clinical and myopathological reevaluation of the five affected children, positional cloning, immunofluorescence, and Western blot studies were performed.

RESULTS: All children presented with congenital muscle weakness and childhood-onset fatal dilated cardiomyopathy. Skeletal muscle biopsies showed minicores, centrally located nuclei, and/or dystrophic lesions. In each family, we identified a homozygous titin deletion in exons encoding the C-terminal M-line region. Both deletions cause a frameshift downstream of the titin kinase domain and protein truncation. Immunofluorescence confirmed that truncated titins lacking the C-terminal end were incorporated into sarcomeres. Calpain 3 was secondarily depleted.

INTERPRETATION: M-line titin homozygous truncations cause the first congenital and purely recessive titinopathy, and the first to involve both cardiac and skeletal muscle. These results expand the spectrum of early-onset myopathies and suggest that titin segments downstream of the kinase domain are dispensable for skeletal and cardiac muscle development, but are crucial for maintaining sarcomere integrity.

Original language	English
Pages (from-to)	340-351
Number of pages	12
Journal	Annals of Neurology
Volume	61
Issue number	4
DOIs	https://doi.org/10.1002/ana.21089
Publication status	Published - Apr 2007

Keywords

Adolescent
Adult
Age of Onset
Calpain
Cardiomyopathies
Child
Chromosomes, Human, Pair 2
Connectin
DNA Mutational Analysis
Exons
Family Health
Gene Deletion
Genetic Linkage
Genotype
Humans
Male
Molecular Sequence Data
Muscle Proteins
Muscles
Phenotype
Protein Kinases
Protein Structure, Tertiary

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Carmignac, V., Salih, M. A. M., Quijano-Roy, S., Marchand, S., Al Rayess, M. M., Mukhtar, M. M., Urtizberea, J. A., Labeit, S., Guicheney, P., Leturcq, F., Gautel, M., Fardeau, M., Campbell, K. P., Richard, I., Estournet, B., & Ferreiro, A. (2007). C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Annals of Neurology, 61(4), 340-351. https://doi.org/10.1002/ana.21089

@article{a904d8f7e71d4d04a8bf6a6e9199b28b,

title = "C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy",

abstract = "OBJECTIVE: The giant protein titin is essential for striated muscle development, structure, and elasticity. All titin mutations reported to date cause late-onset, dominant disorders involving either skeletal muscle or the heart. Our aim was to delineate the phenotype and determine the genetic defects in two consanguineous families with an early-onset, recessive muscle and cardiac disorder.METHODS: Clinical and myopathological reevaluation of the five affected children, positional cloning, immunofluorescence, and Western blot studies were performed.RESULTS: All children presented with congenital muscle weakness and childhood-onset fatal dilated cardiomyopathy. Skeletal muscle biopsies showed minicores, centrally located nuclei, and/or dystrophic lesions. In each family, we identified a homozygous titin deletion in exons encoding the C-terminal M-line region. Both deletions cause a frameshift downstream of the titin kinase domain and protein truncation. Immunofluorescence confirmed that truncated titins lacking the C-terminal end were incorporated into sarcomeres. Calpain 3 was secondarily depleted.INTERPRETATION: M-line titin homozygous truncations cause the first congenital and purely recessive titinopathy, and the first to involve both cardiac and skeletal muscle. These results expand the spectrum of early-onset myopathies and suggest that titin segments downstream of the kinase domain are dispensable for skeletal and cardiac muscle development, but are crucial for maintaining sarcomere integrity.",

keywords = "Adolescent, Adult, Age of Onset, Calpain, Cardiomyopathies, Child, Chromosomes, Human, Pair 2, Connectin, DNA Mutational Analysis, Exons, Family Health, Gene Deletion, Genetic Linkage, Genotype, Humans, Male, Molecular Sequence Data, Muscle Proteins, Muscles, Phenotype, Protein Kinases, Protein Structure, Tertiary",

author = "Virginie Carmignac and Salih, {Mustafa A M} and Susana Quijano-Roy and Sylvie Marchand and {Al Rayess}, {Molham M} and Mukhtar, {Maowia M} and Urtizberea, {Jon A} and Siegfried Labeit and Pascale Guicheney and France Leturcq and Mathias Gautel and Michel Fardeau and Campbell, {Kevin P} and Isabelle Richard and Brigitte Estournet and Ana Ferreiro",

year = "2007",

month = apr,

doi = "10.1002/ana.21089",

language = "English",

volume = "61",

pages = "340--351",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley and Sons Inc.",

number = "4",

}

Carmignac, V, Salih, MAM, Quijano-Roy, S, Marchand, S, Al Rayess, MM, Mukhtar, MM, Urtizberea, JA, Labeit, S, Guicheney, P, Leturcq, F, Gautel, M, Fardeau, M, Campbell, KP, Richard, I, Estournet, B & Ferreiro, A 2007, 'C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy', Annals of Neurology, vol. 61, no. 4, pp. 340-351. https://doi.org/10.1002/ana.21089

TY - JOUR

T1 - C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy

AU - Carmignac, Virginie

AU - Salih, Mustafa A M

AU - Quijano-Roy, Susana

AU - Marchand, Sylvie

AU - Al Rayess, Molham M

AU - Mukhtar, Maowia M

AU - Urtizberea, Jon A

AU - Labeit, Siegfried

AU - Guicheney, Pascale

AU - Leturcq, France

AU - Gautel, Mathias

AU - Fardeau, Michel

AU - Campbell, Kevin P

AU - Richard, Isabelle

AU - Estournet, Brigitte

AU - Ferreiro, Ana

PY - 2007/4

Y1 - 2007/4

N2 - OBJECTIVE: The giant protein titin is essential for striated muscle development, structure, and elasticity. All titin mutations reported to date cause late-onset, dominant disorders involving either skeletal muscle or the heart. Our aim was to delineate the phenotype and determine the genetic defects in two consanguineous families with an early-onset, recessive muscle and cardiac disorder.METHODS: Clinical and myopathological reevaluation of the five affected children, positional cloning, immunofluorescence, and Western blot studies were performed.RESULTS: All children presented with congenital muscle weakness and childhood-onset fatal dilated cardiomyopathy. Skeletal muscle biopsies showed minicores, centrally located nuclei, and/or dystrophic lesions. In each family, we identified a homozygous titin deletion in exons encoding the C-terminal M-line region. Both deletions cause a frameshift downstream of the titin kinase domain and protein truncation. Immunofluorescence confirmed that truncated titins lacking the C-terminal end were incorporated into sarcomeres. Calpain 3 was secondarily depleted.INTERPRETATION: M-line titin homozygous truncations cause the first congenital and purely recessive titinopathy, and the first to involve both cardiac and skeletal muscle. These results expand the spectrum of early-onset myopathies and suggest that titin segments downstream of the kinase domain are dispensable for skeletal and cardiac muscle development, but are crucial for maintaining sarcomere integrity.

AB - OBJECTIVE: The giant protein titin is essential for striated muscle development, structure, and elasticity. All titin mutations reported to date cause late-onset, dominant disorders involving either skeletal muscle or the heart. Our aim was to delineate the phenotype and determine the genetic defects in two consanguineous families with an early-onset, recessive muscle and cardiac disorder.METHODS: Clinical and myopathological reevaluation of the five affected children, positional cloning, immunofluorescence, and Western blot studies were performed.RESULTS: All children presented with congenital muscle weakness and childhood-onset fatal dilated cardiomyopathy. Skeletal muscle biopsies showed minicores, centrally located nuclei, and/or dystrophic lesions. In each family, we identified a homozygous titin deletion in exons encoding the C-terminal M-line region. Both deletions cause a frameshift downstream of the titin kinase domain and protein truncation. Immunofluorescence confirmed that truncated titins lacking the C-terminal end were incorporated into sarcomeres. Calpain 3 was secondarily depleted.INTERPRETATION: M-line titin homozygous truncations cause the first congenital and purely recessive titinopathy, and the first to involve both cardiac and skeletal muscle. These results expand the spectrum of early-onset myopathies and suggest that titin segments downstream of the kinase domain are dispensable for skeletal and cardiac muscle development, but are crucial for maintaining sarcomere integrity.

KW - Adolescent

KW - Adult

KW - Age of Onset

KW - Calpain

KW - Cardiomyopathies

KW - Child

KW - Chromosomes, Human, Pair 2

KW - Connectin

KW - DNA Mutational Analysis

KW - Exons

KW - Family Health

KW - Gene Deletion

KW - Genetic Linkage

KW - Genotype

KW - Humans

KW - Male

KW - Molecular Sequence Data

KW - Muscle Proteins

KW - Muscles

KW - Phenotype

KW - Protein Kinases

KW - Protein Structure, Tertiary

U2 - 10.1002/ana.21089

DO - 10.1002/ana.21089

M3 - Article

C2 - 17444505

SN - 0364-5134

VL - 61

SP - 340

EP - 351

JO - Annals of Neurology

JF - Annals of Neurology

IS - 4

ER -

C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy

Abstract

Keywords

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