Journal article
Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy
Acta neuropathologica, Vol.133(4), pp.517-533
04/2017
DOI: 10.1007/s00401-016-1656-8
PMID: 28012042
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 Ca
channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca
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 (Ca
1.1), 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 Ca
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.
Details
- Title: Subtitle
- Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy
- Creators
- Vanessa Schartner - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)Norma B Romero - GH Pitié-SalpêtrièreSandra Donkervoort - National Institutes of HealthSusan Treves - University Hospital of BaselPinki Munot - UCL Institute of Child HealthTyler Mark Pierson - Cedars-Sinai Medical CenterIvana Dabaj - Assistance Publique des Hôpitaux de Paris (AP-HP), Service de Pédiatrie, Hôpital Raymond Poincaré, Hôpitaux Universitaires Paris-Ile-de-France Ouest, Garches, FranceEdoardo Malfatti - GH Pitié-SalpêtrièreIrina T Zaharieva - UCL Institute of Child HealthFrancesco Zorzato - University Hospital of BaselOsorio Abath Neto - National Institute of Neurological Disorders and StrokeGuy Brochier - GH Pitié-SalpêtrièreXavière Lornage - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)Bruno Eymard - Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.Ana Lía Taratuto - Consultant-Neuropathology Department, National Pediatric Hospital J-P-Garrahan and Institute for Neurological Research-FLENI, Buenos Aires, Argentina.Johann Böhm - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)Hernan Gonorazky - University of TorontoLeigh Ramos-Platt - University of Southern CaliforniaLucy Feng - UCL Institute of Child HealthRahul Phadke - Great Ormond Street HospitalDiana X Bharucha-Goebel - National Institutes of HealthCharlotte Jane Sumner - Johns Hopkins MedicineMai Thao Bui - GH Pitié-SalpêtrièreEmmanuelle Lacene - GH Pitié-SalpêtrièreMaud Beuvin - GH Pitié-SalpêtrièreClémence Labasse - GH Pitié-SalpêtrièreNicolas Dondaine - Nouvel Hôpital CivilRaphael Schneider - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)Julie Thompson - ICube-UMR7357, CSTB Complex Systems and Translational BioinformaticsAnne Boland - Centre National de Recherche en Génomique HumaineJean-François Deleuze - Centre National de Recherche en Génomique HumaineEmma Matthews - Great Ormond Street HospitalAleksandra Nadaj Pakleza - Centre Hospitalier Universitaire d'AngersCaroline A Sewry - UCL Institute of Child HealthValérie Biancalana - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)Susana Quijano-Roy - InsermFrancesco Muntoni - UCL Institute of Child HealthMichel Fardeau - GH Pitié-SalpêtrièreCarsten G Bönnemann - National Institutes of HealthJocelyn Laporte - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
- Resource Type
- Journal article
- Publication Details
- Acta neuropathologica, Vol.133(4), pp.517-533
- DOI
- 10.1007/s00401-016-1656-8
- PMID
- 28012042
- NLM abbreviation
- Acta Neuropathol
- ISSN
- 0001-6322
- eISSN
- 1432-0533
- Grant note
- name: Institut National de la Santé et de la Recherche Médicale (INSERM); DOI: 10.13039/501100004794, name: Centre National de la Recherche Scientifique (CNRS), ; DOI: 10.13039/501100003768, name: Université de Strasbourg; DOI: 10.13039/501100005304, name: Agence Nationale pour le Développement de la Recherche en Santé, award: ANR-10-INBS-09; DOI: 10.13039/100014865, name: Fondation Maladies Rares, award: ANR-10-LABX-0030-INRT; name: Investissements d'Avenir, award: ANR-10-IDEX-0002-02; DOI: 10.13039/100007393, name: Association Française contre les Myopathies, award: AFM-17088; DOI: 10.13039/100005202, name: Muscular Dystrophy Association, award: MDA-186985; DOI: 10.13039/501100000658, name: Myotubular Trust; name: Sparks the Children’s medical research charity, award: N° 12KCL 01-MT; DOI: 10.13039/501100001711, name: swiss national science foundation, award: 31003A-146198; name: Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship; name: National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust; DOI: 10.13039/501100000765, name: University College London
- Language
- English
- Date published
- 04/2017
- Academic Unit
- Pathology
- Record Identifier
- 9984277265802771
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