Early onset collagen VI myopathies: Genetic and clinical correlations

Authors

  • Laura Briñas PhD,

    1. Inserm, U582, Paris, France
    2. UPMC University of Paris 06, IFR14, Myology Institute, Paris, France
    Current affiliation:
    1. UPMC University Paris 06, Institut de Myologie, Inserm, U974 and CNRS, UMR7215, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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    • L.B. and P.R. contributed equally.

  • Pascale Richard PhD,

    1. Inserm, U582, Paris, France
    2. UPMC University of Paris 06, IFR14, Myology Institute, Paris, France
    3. AP-HP, Pitié -Salpêtrière Hospital Group, Cardiogenetics and Myogenetics Functional Unit, Metabolic Biochemistry Division, Paris, France
    Current affiliation:
    1. Inserm U956, CHU Pitié Salpêtrière, Paris, France
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    • L.B. and P.R. contributed equally.

  • Susana Quijano-Roy MD, PhD,

    1. Inserm, U582, Paris, France
    2. UPMC University of Paris 06, IFR14, Myology Institute, Paris, France
    3. Assistance Publique-Hôpitaux de Paris, Pediatric Division, Neuromuscular Disease Reference Center, Raymond Poincaré Hospital, Garches, France
    Current affiliation:
    1. UPMC University Paris 06, Institut de Myologie, Inserm, U974 and CNRS, UMR7215, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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  • Corine Gartioux BS,

    1. Inserm, U582, Paris, France
    2. UPMC University of Paris 06, IFR14, Myology Institute, Paris, France
    Current affiliation:
    1. UPMC University Paris 06, Institut de Myologie, Inserm, U974 and CNRS, UMR7215, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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  • Céline Ledeuil BS,

    1. AP-HP, Pitié -Salpêtrière Hospital Group, Cardiogenetics and Myogenetics Functional Unit, Metabolic Biochemistry Division, Paris, France
    Current affiliation:
    1. Inserm U956, CHU Pitié Salpêtrière, Paris, France
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  • Emmanuelle Lacène BS,

    1. Inserm, U582, Paris, France
    2. UPMC University of Paris 06, IFR14, Myology Institute, Paris, France
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  • Samira Makri MD,

    1. Neurology Division, Ali Ait Idir Specialized Hospital, Alger, Algeria
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  • Ana Ferreiro MD, PhD,

    1. Inserm, U582, Paris, France
    2. UPMC University of Paris 06, IFR14, Myology Institute, Paris, France
    3. Assistance Publique-Hôpitaux de Paris, Pediatric Division, Neuromuscular Disease Reference Center, Raymond Poincaré Hospital, Garches, France
    4. Paris-Est Neuromuscular Disease Referal Centre, Myology Institute, Pitié-Salpêtrière Hospital Group, Paris, France
    Current affiliation:
    1. Inserm, U787-Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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  • Svetlana Maugenre BS,

    1. Inserm, U582, Paris, France
    2. UPMC University of Paris 06, IFR14, Myology Institute, Paris, France
    Current affiliation:
    1. Inserm U956, CHU Pitié Salpêtrière, Paris, France
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  • Haluk Topaloglu MD,

    1. Section of Neurology, Department of Pediatrics, Hacettepe Children's Hospital, Ankara, Turkey
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  • Göknur Haliloglu MD,

    1. Section of Neurology, Department of Pediatrics, Hacettepe Children's Hospital, Ankara, Turkey
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  • Isabelle Pénisson-Besnier MD,

    1. Neuromuscular Disease Reference Center, Department of Neurology, University Hospital, Angers, France
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  • Pierre-Yves Jeannet MD,

    1. Neuropediatry Division, CHUV-BH11, Lausanne, Switzerland
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  • Luciano Merlini MD,

    1. Department of Experimental and Diagnostic Medicine, Section of Medical Genetics, University of Ferrara, Ferrara, Italy
    2. Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute, Bologna, Italy
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  • Carmen Navarro MD, PhD,

    1. Department of Pathological Anatomy, Hospital Meixoeiro, Vigo University Hospital, Vigo, Spain
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  • Annick Toutain MD, PhD,

    1. Genetics Division, Bretonneau University Hospital, Tours, France
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  • Denys Chaigne MD,

    1. Cliniq Sainte-Odile, Strasbourg, France
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  • Isabelle Desguerre MD,

    1. Assistance Publique-Hôpitaux de Paris, Department of Neuropediatrics, Neuromuscular Disease Reference Center “Garches-Necker-Mondor-Hendaye,” Necker-Enfants Malades Hospital, Paris, France
    2. Department of Neurosciences, Team 10 Inserm, U841 Mondor Biomedical Research Institute, Paris XII University, Créteil, France
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  • Christine de Die-Smulders MD,

    1. Department of Clinical Genetics, University Hospital Maastricht, Maastricht, the Netherlands
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  • Murielle Dunand MD,

    1. Nerve-Muscle Unit, Neurology Division, BH07/309, University Hospital Vaudois, Lausanne, Switzerland
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  • Bernard Echenne MD, PhD,

    1. University Hospital of Montpellier, Neuropediatry Division-Grand Sud Ouest Neuromuscular Disease Reference Center, Gui de Chauliac Hospital, Montpellier, France
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  • Bruno Eymard MD, PhD,

    1. Paris-Est Neuromuscular Disease Referal Centre, Myology Institute, Pitié-Salpêtrière Hospital Group, Paris, France
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  • Thierry Kuntzer MD,

    1. Nerve-Muscle Unit, Neurology Division, BH07/309, University Hospital Vaudois, Lausanne, Switzerland
    Current affiliation:
    1. UPMC University Paris 06, Institut de Myologie, Inserm, U974 and CNRS, UMR7215, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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  • Kim Maincent MD,

    1. Armand Trousseau Hospital, Neuropediatry Division, Neuromuscular Disease Center, Paris, France
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  • Michèle Mayer MD,

    1. Armand Trousseau Hospital, Neuropediatry Division, Neuromuscular Disease Center, Paris, France
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  • Ghislaine Plessis MD,

    1. Medical Genetics Division, DGR, Clémenceau University Hospital, Caen, France
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  • François Rivier MD, PhD,

    1. University Hospital of Montpellier, Neuropediatry Division-Grand Sud Ouest Neuromuscular Disease Reference Center, Gui de Chauliac Hospital, Montpellier, France
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  • Filip Roelens MD,

    1. Dominiek Savio Instituut Gits, Roeselare, Belgium
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  • Tanya Stojkovic MD,

    1. Paris-Est Neuromuscular Disease Referal Centre, Myology Institute, Pitié-Salpêtrière Hospital Group, Paris, France
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  • Ana Lía Taratuto MD, PhD,

    1. Department of Neuropathology/FLENI, Institute for Neurological Research, Buenos Aires, Argentina
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  • Fabiana Lubieniecki MD,

    1. Department of Pathology, Garrahan National Pediatric Hospital, Buenos Aires, Argentina
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  • Soledad Monges MD,

    1. Department of Neuropediatrics, Garrahan National Pediatric Hospital, Buenos Aires, Argentina
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  • Christine Tranchant MD,

    1. Neurology Division, Strasbourg University Hospitals, Strasbourg, France
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  • Louis Viollet MD, PhD,

    1. Assistance Publique-Hôpitaux de Paris, Pediatric Division, Neuromuscular Disease Reference Center, Raymond Poincaré Hospital, Garches, France
    2. Inserm, U781, Necker-Enfants Malades Hospital, Paris, France. Additional Supporting Information can be found in the online version of this article
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  • Norma B. Romero MD, PhD,

    1. Inserm, U582, Paris, France
    2. UPMC University of Paris 06, IFR14, Myology Institute, Paris, France
    Current affiliation:
    1. UPMC University Paris 06, Institut de Myologie, Inserm, U974 and CNRS, UMR7215, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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  • Brigitte Estournet MD, PhD,

    1. Assistance Publique-Hôpitaux de Paris, Pediatric Division, Neuromuscular Disease Reference Center, Raymond Poincaré Hospital, Garches, France
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  • Pascale Guicheney PhD,

    1. Inserm, U582, Paris, France
    2. UPMC University of Paris 06, IFR14, Myology Institute, Paris, France
    3. AP-HP, Pitié -Salpêtrière Hospital Group, Cardiogenetics and Myogenetics Functional Unit, Metabolic Biochemistry Division, Paris, France
    Current affiliation:
    1. Inserm U956, CHU Pitié Salpêtrière, Paris, France
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    • P.G. and V. A. contributed equally.

  • Valérie Allamand PhD

    Corresponding author
    1. Inserm, U582, Paris, France
    2. UPMC University of Paris 06, IFR14, Myology Institute, Paris, France
    Current affiliation:
    1. UPMC University Paris 06, Institut de Myologie, Inserm, U974 and CNRS, UMR7215, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
    • UMRS 974, Institut de Myologie, Bˆt. Babinski, GH Pitié Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris cedex 13, France
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    • P.G. and V. A. contributed equally.


Abstract

Objective

Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype-phenotype correlations.

Methods

Patients were classified into 3 groups: early-severe (18%), moderate-progressive (53%), and mild (29%). ColVI secretion was analyzed in patient-derived skin fibroblasts. Chain-specific transcript levels were quantified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and mutation identification was performed by sequencing of complementary DNA.

Results

ColVI secretion was altered in all fibroblast cultures studied. We identified 56 mutations, mostly novel and private. Dominant de novo mutations were detected in 61% of the cases. Importantly, mutations causing premature termination codons (PTCs) or in-frame insertions strikingly destabilized the corresponding transcripts. Homozygous PTC-causing mutations in the triple helix domains led to the most severe phenotypes (ambulation never achieved), whereas dominant de novo in-frame exon skipping and glycine missense mutations were identified in patients of the moderate-progressive group (loss of ambulation).

Interpretation

This work emphasizes that the diagnosis of early onset ColVI myopathies is arduous and time-consuming, and demonstrates that quantitative RT-PCR is a helpful tool for the identification of some mutation-bearing genes. Moreover, the clinical classification proposed allowed genotype-phenotype relationships to be explored, and may be useful in the design of future clinical trials. ANN NEUROL 2010;68:511–520

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