Journal article
C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy
Annals of neurology, Vol.61(4), pp.340-351
2007
DOI: 10.1002/ana.21089
PMID: 17444505
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.
Details
- Title: Subtitle
- C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy
- Creators
- Virginie CARMIGNAC - Institut National de la Sante et de la Recherche Médicale U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, FranceMustafa A. M SALIH - Division of Pedi atric Neurology, Department of Pediatrics, College of Medicine, Riyadh, Saudi ArabiaMathias GAUTEL - Muscle Signalling and Development, The Randall Division of Cell and Molecular Biophysics and the Cardiovascular Division, New Hunt's House, King's College London, London, United KingdomMichel FARDEAU - Institut National de la Sante et de la Recherche Médicale U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, FranceKevin P CAMPBELL - Howatd Hughes Medical Institute, Department of Physiology and Biophys ics, Internal Medicine, and Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, United StatesIsabelle RICHARD - Généthon, Centre National de la Recherche Scientifique, Unité Mixte de Recherche, 8115, Evry, FranceBrigitte ESTOURNET - Service de Pédiatrie -Réanimation Infantile, Hôpital Raymond Poincaré, Garches, FranceAna FERREIRO - Institut National de la Sante et de la Recherche Médicale U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, FranceSusana QUIJANO-ROY - Institut National de la Sante et de la Recherche Médicale U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, FranceSylvie MARCHAND - Généthon, Centre National de la Recherche Scientifique, Unité Mixte de Recherche, 8115, Evry, FranceMolham M AL RAYESS - Department of Pathology, College of Medi cine, Riyadh, Saudi ArabiaMaowia M MUKHTAR - Institute of Endemic Diseases, Univer sity of Khartoum, Khartoum, SudanJon A URTIZBEREA - Hôpital Marin, Hendaye, FranceSiegfried LABEIT - Institute for Anaesthesiology and Intensive Care, University Clinic Mannheim, Mannheim, GermanyPascale GUICHENEY - Institut National de la Sante et de la Recherche Médicale U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, FranceFrance LETURCQ - Laboratoire de Bio chimie Génétique, Hôpital Cochin, Paris, France
- Resource Type
- Journal article
- Publication Details
- Annals of neurology, Vol.61(4), pp.340-351
- Publisher
- Willey-Liss; Hoboken
- DOI
- 10.1002/ana.21089
- PMID
- 17444505
- ISSN
- 0364-5134
- eISSN
- 1531-8249
- Language
- English
- Date published
- 2007
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984020998302771
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