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

Authors

  • Virginie Carmignac MS,

    1. Institut National de la Sante et de la Recherche Médicale U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, France
    2. Université Pierre et Marie Curie, Paris, France
    Search for more papers by this author
  • Mustafa A. M. Salih MD,

    1. Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, Riyadh, Saudi Arabia
    Search for more papers by this author
  • Susana Quijano-Roy MD, PhD,

    1. Institut National de la Sante et de la Recherche Médicale U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, France
    2. Université Pierre et Marie Curie, Paris, France
    3. Service de Pédiatrie-Réanimation Infantile, Hôpital Raymond Poincaré, Garches, France
    Search for more papers by this author
  • Sylvie Marchand PhD,

    1. Généthon, Centre National de la Recherche Scientifique, Unité Mixte de Recherche, 8115, Evry, France
    Search for more papers by this author
  • Molham M. Al Rayess MD, FCAP,

    1. Department of Pathology, College of Medicine, Riyadh, Saudi Arabia
    Search for more papers by this author
  • Maowia M. Mukhtar PhD,

    1. Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan
    Search for more papers by this author
  • Jon A. Urtizberea MD,

    1. Hôpital Marin, Hendaye, France
    Search for more papers by this author
  • Siegfried Labeit MD,

    1. Institute for Anaesthesiology and Intensive Care, University Clinic Mannheim, Mannheim, Germany
    Search for more papers by this author
  • Pascale Guicheney PhD,

    1. Institut National de la Sante et de la Recherche Médicale U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, France
    2. Université Pierre et Marie Curie, Paris, France
    Search for more papers by this author
  • France Leturcq PhD,

    1. Laboratoire de Biochimie Génétique, Hôpital Cochin, Paris, France
    Search for more papers by this author
  • Mathias Gautel MD, PhD,

    1. 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 Kingdom
    Search for more papers by this author
  • Michel Fardeau MD, PhD,

    1. Institut National de la Sante et de la Recherche Médicale U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, France
    2. Université Pierre et Marie Curie, Paris, France
    Search for more papers by this author
  • Kevin P. Campbell PhD,

    1. Howard Hughes Medical Institute, Department of Physiology and Biophysics, Internal Medicine Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA
    Search for more papers by this author
  • Isabelle Richard PhD,

    1. Généthon, Centre National de la Recherche Scientifique, Unité Mixte de Recherche, 8115, Evry, France
    Search for more papers by this author
  • Brigitte Estournet MD,

    1. Service de Pédiatrie-Réanimation Infantile, Hôpital Raymond Poincaré, Garches, France
    Search for more papers by this author
  • Ana Ferreiro MD, PhD

    Corresponding author
    1. Institut National de la Sante et de la Recherche Médicale U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, France
    2. Université Pierre et Marie Curie, Paris, France
    • INSERM U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, 47 Boulevard de l'Hôpital, 75651 Paris, France
    Search for more papers by this author

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. Ann Neurol 2007;61:340–351

Ancillary