Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy
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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.
KeywordsDHPR Congenital myopathy Excitation–contraction coupling Triad Centronuclear myopathy Core myopathy Myotubular myopathy
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.
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