Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy
| Autor: | Emma Matthews, Edoardo Malfatti, Osorio Abath Neto, Sandra Donkervoort, Aleksandra Nadaj Pakleza, Bruno Eymard, Hernan Gonorazky, F Zorzato, Lucy Feng, Mai Thao Bui, Pinki Munot, Johann Böhm, Nicolas Dondaine, Guy Brochier, Anne Boland, Valérie Biancalana, Clémence Labasse, Ana Lia Taratuto, Susan Treves, Leigh Ramos-Platt, Emmanuelle Lacène, Xavière Lornage, Charlotte J. Sumner, Caroline Sewry, Vanessa Schartner, Julie D. Thompson, Jocelyn Laporte, Tyler Mark Pierson, Michel Fardeau, Irina Zaharieva, Susana Quijano-Roy, Rahul Phadke, Norma B. Romero, Diana Bharucha-Goebel, Maud Beuvin, Francesco Muntoni, Jean-François Deleuze, Carsten G. Bönnemann, Raphaël Schneider, Ivana Dabaj |
|---|---|
| Přispěvatelé: | Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Triad Sequence Homology Core myopathy Muscle Cells/metabolism/pathology Cohort Studies 0302 clinical medicine Child Myotonia Congenita/diagnostic imaging/*genetics/*metabolism/pathology Cells Cultured Congenital myopathy Cultured Ryanodine receptor Malignant hyperthermia Middle Aged musculoskeletal system Amino Acid Myotubular myopathy medicine.anatomical_structure Phenotype Muscle Female medicine.symptom Muscle contraction Adult medicine.medical_specialty Calcium/metabolism Adolescent Calcium Channels L-Type Myotonia Congenita Cells Biology Skeletal/diagnostic imaging/metabolism/pathology NO Pathology and Forensic Medicine Excitation–contraction coupling 03 medical and health sciences Cellular and Molecular Neuroscience Young Adult Hypokalemic periodic paralysis Internal medicine medicine Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Family Calcium Channels/*genetics/*metabolism Centronuclear myopathy Muscle Skeletal RYR1 Muscle Cells Sequence Homology Amino Acid DHPR Skeletal muscle medicine.disease Excitation-contraction coupling 030104 developmental biology Endocrinology Mutation Calcium Neurology (clinical) Calcium Channels 030217 neurology & neurosurgery |
| Zdroj: | Acta Neuropathologica Acta Neuropathologica, 2017, 133 (4), pp.517-533. ⟨10.1007/s00401-016-1656-8⟩ |
| ISSN: | 1432-0533 0001-6322 |
| DOI: | 10.1007/s00401-016-1656-8⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink