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Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy

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Abstract

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.

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Acknowledgements

We thank Isabelle Marty for triadin antibody, John Rendu for RYR1 molecular testing, Anne-Sophie Nicot and Clara Franzini-Armstrong for discussions, Robert Y. Carlier for analysis of MRI images, and Nicola Foulds for clinical discussions. This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), University of Strasbourg, the France Génomique National infrastructure, funded as part of the Investissements d’Avenir program managed by the Agence Nationale pour la Recherche (ANR-10-INBS-09), and by Fondation Maladies Rares within the frame of the “Myocapture” sequencing project, ANR-10-LABX-0030-INRT under the frame program Investissements d’Avenir ANR-10-IDEX-0002-02, Association Française contre les Myopathies (AFM-17088), Muscular Dystrophy Association (MDA-186985), Myotubular Trust and Sparks the Children’s medical research charity grant N° 12KCL 01-MT, and the Swiss National Science Foundation grant N° 31003A-146198. T.M.P. was supported by the Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases. F.M. is supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. The Biobank of the MRC Neuromuscular Centre and the support of the Muscular Dystrophy UK to the Dubowitz Neuromuscular Centre are also gratefully acknowledged.

Web resources

ExAC Browser/Exome Aggregation Consortium (URL: http://exac.broadinstitute.org/). Exome Variant Server (URL: http://evs.gs.washington.edu/EVS/) [March, 2012]). 1000 genomes (URL: http://www.1000genomes.org/). Database of Single Nucleotide Polymorphisms (dbSNP Build ID: 134) (URL: http://www.ncbi.nlm.nih.gov/SNP/). Online Mendelian Inheritance in Man (OMIM) (URL: http://www.omim.org/).

Author information

Author notes

  1. Hernan Gonorazky

    Present address: Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France

    Vanessa Schartner, Osorio Abath Neto, Xavière Lornage, Johann Böhm, Raphael Schneider, Valérie Biancalana & Jocelyn Laporte

  2. INSERM U964, 67404, Illkirch, France

    Vanessa Schartner, Xavière Lornage, Johann Böhm, Raphael Schneider, Valérie Biancalana & Jocelyn Laporte

  3. CNRS, UMR7104, 67404, Illkirch, France

    Vanessa Schartner, Xavière Lornage, Johann Böhm, Raphael Schneider, Valérie Biancalana & Jocelyn Laporte

  4. Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404, Illkirch, France

    Vanessa Schartner, Xavière Lornage, Johann Böhm, Raphael Schneider, Valérie Biancalana & Jocelyn Laporte

  5. 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

    Norma B. Romero, Edoardo Malfatti, Guy Brochier, Mai Thao Bui, Emmanuelle Lacene, Maud Beuvin, Clémence Labasse & Michel Fardeau

  6. Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France

    Norma B. Romero, Edoardo Malfatti, Guy Brochier, Mai Thao Bui, Emmanuelle Lacene, Maud Beuvin, Clémence Labasse & Michel Fardeau

  7. 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

    Sandra Donkervoort, Osorio Abath Neto, Diana X. Bharucha-Goebel & Carsten G. Bönnemann

  8. Department of Anesthesia, Universitätsspital Basel, 4031, Basel, Switzerland

    Susan Treves & Francesco Zorzato

  9. Department of Biomedizin, Universitätsspital Basel, 4031, Basel, Switzerland

    Susan Treves & Francesco Zorzato

  10. Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK

    Pinki Munot, Irina T. Zaharieva, Lucy Feng, Rahul Phadke, Emma Matthews, Caroline A. Sewry & Francesco Muntoni

  11. Departments of Pediatrics and Neurology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, 90048, USA

    Tyler Mark Pierson

  12. The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, 90048, USA

    Tyler Mark Pierson

  13. Assistance Publique des Hôpitaux de Paris (AP-HP), Service de Pédiatrie, Hôpital Raymond Poincaré, Hôpitaux Universitaires Paris-Ile-de-France Ouest, Garches, France

    Ivana Dabaj & Susana Quijano-Roy

  14. Centre de Référence de Maladies Neuromusculaires Garches-Necker-Mondor-Hendaye (GNMH), Garches, France

    Ivana Dabaj & Susana Quijano-Roy

  15. Réseau National Français de la Filière Neuromusculaire (FILNEMUS), Garches, France

    Ivana Dabaj & Susana Quijano-Roy

  16. Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    Bruno Eymard

  17. Consultant-Neuropathology Department, National Pediatric Hospital J-P-Garrahan and Institute for Neurological Research-FLENI, Buenos Aires, Argentina

    Ana Lía Taratuto

  18. 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

    Leigh Ramos-Platt

  19. Division of Neurology, Children’s National Health System, Washington, DC, 20010, USA

    Diana X. Bharucha-Goebel

  20. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Charlotte Jane Sumner

  21. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Charlotte Jane Sumner

  22. Faculté de Médecine, ICube-UMR7357, CSTB Complex Systems and Translational Bioinformatics, 67000, Strasbourg, France

    Raphael Schneider & Julie Thompson

  23. Centre National de Génotypage, Institut de Génomique, CEA, Evry, France

    Anne Boland & Jean-François Deleuze

  24. Centre de référence des maladies neuromusculaires Nantes/Angers, Service de Neurologie, CHU Angers, Angers, France

    Aleksandra Nadaj Pakleza

  25. Laboratoire de Diagnostic Génétique, Faculté de Médecine, Nouvel Hôpital Civil, 67000, Strasbourg, France

    Nicolas Dondaine & Valérie Biancalana

  26. Université de Versailles-St Quentin, U1179 UVSQ-INSERM, Montigny, France

    Susana Quijano-Roy

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Corresponding author

Correspondence to Jocelyn Laporte.

Additional information

V. Schartner and N. B. Romero contributed equally.

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Schartner, V., Romero, N.B., Donkervoort, S. et al. Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy. Acta Neuropathol 133, 517–533 (2017). https://doi.org/10.1007/s00401-016-1656-8

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  • DOI: https://doi.org/10.1007/s00401-016-1656-8

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