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Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy.

  • Schartner V Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.
  • Romero NB Université Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, 47 Boulevard de l'hôpital, 75013, Paris, France.
  • Donkervoort S Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892-1477, USA.
  • Treves S Department of Anesthesia, Universitätsspital Basel, 4031, Basel, Switzerland.
  • Munot P Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
  • Pierson TM Departments of Pediatrics and Neurology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, 90048, USA.
  • Dabaj I Assistance Publique des Hôpitaux de Paris (AP-HP), Service de Pédiatrie, Hôpital Raymond Poincaré, Hôpitaux Universitaires Paris-Ile-de-France Ouest, Garches, France.
  • Malfatti E Université Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, 47 Boulevard de l'hôpital, 75013, Paris, France.
  • Zaharieva IT Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
  • Zorzato F Department of Anesthesia, Universitätsspital Basel, 4031, Basel, Switzerland.
  • Abath Neto O Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.
  • Brochier G Université Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, 47 Boulevard de l'hôpital, 75013, Paris, France.
  • Lornage X Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.
  • Eymard B Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
  • Taratuto AL Consultant-Neuropathology Department, National Pediatric Hospital J-P-Garrahan and Institute for Neurological Research-FLENI, Buenos Aires, Argentina.
  • Böhm J Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.
  • Gonorazky H Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
  • Ramos-Platt L Division of Neurology at Children's Hospital of Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, 4650 W. Sunset Blvd, Mailstop #34, Los Angeles, CA, 90027, USA.
  • Feng L Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
  • Phadke R Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
  • Bharucha-Goebel DX Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892-1477, USA.
  • Sumner CJ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
  • Bui MT Université Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, 47 Boulevard de l'hôpital, 75013, Paris, France.
  • Lacene E Université Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, 47 Boulevard de l'hôpital, 75013, Paris, France.
  • Beuvin M Université Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, 47 Boulevard de l'hôpital, 75013, Paris, France.
  • Labasse C Université Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, 47 Boulevard de l'hôpital, 75013, Paris, France.
  • Dondaine N Laboratoire de Diagnostic Génétique, Faculté de Médecine, Nouvel Hôpital Civil, 67000, Strasbourg, France.
  • Schneider R Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.
  • Thompson J Faculté de Médecine, ICube-UMR7357, CSTB Complex Systems and Translational Bioinformatics, 67000, Strasbourg, France.
  • Boland A Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
  • Deleuze JF Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
  • Matthews E Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
  • Pakleza AN Centre de référence des maladies neuromusculaires Nantes/Angers, Service de Neurologie, CHU Angers, Angers, France.
  • Sewry CA Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
  • Biancalana V Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.
  • Quijano-Roy S Assistance Publique des Hôpitaux de Paris (AP-HP), Service de Pédiatrie, Hôpital Raymond Poincaré, Hôpitaux Universitaires Paris-Ile-de-France Ouest, Garches, France.
  • Muntoni F Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
  • Fardeau M Université Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, 47 Boulevard de l'hôpital, 75013, Paris, France.
  • Bönnemann CG Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892-1477, USA.
  • Laporte J Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France. jocelyn@igbmc.fr.
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  • 2016-12-25
Published in:
  • Acta neuropathologica. - 2017
Centronuclear myopathy
Congenital myopathy
Core myopathy
DHPR
Excitation–contraction coupling
Myotubular myopathy
Triad
Adolescent
Adult
Calcium
Calcium Channels
Calcium Channels, L-Type
Cells, Cultured
Child
Cohort Studies
Family
Female
Humans
Male
Middle Aged
Muscle Cells
Muscle, Skeletal
Mutation
Myotonia Congenita
Phenotype
Sequence Homology, Amino Acid
Young Adult
English Muscle contraction upon nerve stimulation relies on excitation-contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of congenital myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR.
Language
  • English
Open access status
green
Identifiers
Persistent URL
https://sonar.ch/global/documents/102090
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