title: Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy.
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.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.|INSERM U964, 67404, Illkirch, France.|CNRS, UMR7104, 67404, Illkirch, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404, Illkirch, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Schartner
authors.affiliation: 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.|Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Norma B
authors.initials: NB
authors.lastname: Romero
authors.affiliation: 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.
authors.forename: Sandra
authors.initials: S
authors.lastname: Donkervoort
authors.affiliation: Department of Anesthesia, Universitätsspital Basel, 4031, Basel, Switzerland.|Department of Biomedizin, Universitätsspital Basel, 4031, Basel, Switzerland.
authors.forename: Susan
authors.initials: S
authors.lastname: Treves
authors.affiliation: Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Pinki
authors.initials: P
authors.lastname: Munot
authors.affiliation: Departments of Pediatrics and Neurology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, 90048, USA.|The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, 90048, USA.
authors.forename: Tyler Mark
authors.initials: TM
authors.lastname: Pierson
authors.affiliation: Assistance Publique des Hôpitaux de Paris (AP-HP), Service de Pédiatrie, Hôpital Raymond Poincaré, Hôpitaux Universitaires Paris-Ile-de-France Ouest, Garches, France.|Centre de Référence de Maladies Neuromusculaires Garches-Necker-Mondor-Hendaye (GNMH), Garches, France.|Réseau National Français de la Filière Neuromusculaire (FILNEMUS), Garches, France.
authors.forename: Ivana
authors.initials: I
authors.lastname: Dabaj
authors.affiliation: 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.|Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Malfatti
authors.affiliation: Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Irina T
authors.initials: IT
authors.lastname: Zaharieva
authors.affiliation: Department of Anesthesia, Universitätsspital Basel, 4031, Basel, Switzerland.|Department of Biomedizin, Universitätsspital Basel, 4031, Basel, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Zorzato
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.|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.
authors.forename: Osorio
authors.initials: O
authors.lastname: Abath Neto
authors.affiliation: 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.|Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Brochier
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.|INSERM U964, 67404, Illkirch, France.|CNRS, UMR7104, 67404, Illkirch, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404, Illkirch, France.
authors.forename: Xavière
authors.initials: X
authors.lastname: Lornage
authors.affiliation: Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.affiliation: Consultant-Neuropathology Department, National Pediatric Hospital J-P-Garrahan and Institute for Neurological Research-FLENI, Buenos Aires, Argentina.
authors.forename: Ana Lía
authors.initials: AL
authors.lastname: Taratuto
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.|INSERM U964, 67404, Illkirch, France.|CNRS, UMR7104, 67404, Illkirch, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404, Illkirch, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Böhm
authors.affiliation: Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors.forename: Hernan
authors.initials: H
authors.lastname: Gonorazky
authors.affiliation: 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.
authors.forename: Leigh
authors.initials: L
authors.lastname: Ramos-Platt
authors.affiliation: Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Feng
authors.affiliation: Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Rahul
authors.initials: R
authors.lastname: Phadke
authors.affiliation: 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.|Division of Neurology, Children's National Health System, Washington, DC, 20010, USA.
authors.forename: Diana X
authors.initials: DX
authors.lastname: Bharucha-Goebel
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Charlotte Jane
authors.initials: CJ
authors.lastname: Sumner
authors.affiliation: 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.|Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Mai Thao
authors.initials: MT
authors.lastname: Bui
authors.affiliation: 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.|Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Lacene
authors.affiliation: 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.|Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Beuvin
authors.affiliation: 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.|Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Clémence
authors.initials: C
authors.lastname: Labasse
authors.affiliation: Laboratoire de Diagnostic Génétique, Faculté de Médecine, Nouvel Hôpital Civil, 67000, Strasbourg, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dondaine
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.|INSERM U964, 67404, Illkirch, France.|CNRS, UMR7104, 67404, Illkirch, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404, Illkirch, France.|Faculté de Médecine, ICube-UMR7357, CSTB Complex Systems and Translational Bioinformatics, 67000, Strasbourg, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Schneider
authors.affiliation: Faculté de Médecine, ICube-UMR7357, CSTB Complex Systems and Translational Bioinformatics, 67000, Strasbourg, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Boland
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Deleuze
authors.affiliation: Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Matthews
authors.affiliation: Centre de référence des maladies neuromusculaires Nantes/Angers, Service de Neurologie, CHU Angers, Angers, France.
authors.forename: Aleksandra Nadaj
authors.initials: AN
authors.lastname: Pakleza
authors.affiliation: Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Sewry
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.|INSERM U964, 67404, Illkirch, France.|CNRS, UMR7104, 67404, Illkirch, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404, Illkirch, France.|Laboratoire de Diagnostic Génétique, Faculté de Médecine, Nouvel Hôpital Civil, 67000, Strasbourg, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Biancalana
authors.affiliation: Assistance Publique des Hôpitaux de Paris (AP-HP), Service de Pédiatrie, Hôpital Raymond Poincaré, Hôpitaux Universitaires Paris-Ile-de-France Ouest, Garches, France.|Centre de Référence de Maladies Neuromusculaires Garches-Necker-Mondor-Hendaye (GNMH), Garches, France.|Réseau National Français de la Filière Neuromusculaire (FILNEMUS), Garches, France.|Université de Versailles-St Quentin, U1179 UVSQ-INSERM, Montigny, France.
authors.forename: Susana
authors.initials: S
authors.lastname: Quijano-Roy
authors.affiliation: Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: 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.|Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Fardeau
authors.affiliation: 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.
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France. jocelyn@igbmc.fr.|INSERM U964, 67404, Illkirch, France. jocelyn@igbmc.fr.|CNRS, UMR7104, 67404, Illkirch, France. jocelyn@igbmc.fr.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404, Illkirch, France. jocelyn@igbmc.fr.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
mesh_terms: D000293:Adolescent; D000328:Adult; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D002478:Cells, Cultured; D002648:Child; D015331:Cohort Studies; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D032342:Muscle Cells / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009224:Myotonia Congenita / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D055815:Young Adult
chemical_list: C412223:CACNA1S protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002118:Calcium
keywords: Centronuclear myopathy; Congenital myopathy; Core myopathy; DHPR; Excitation–contraction coupling; Myotubular myopathy; Triad