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Acta Neuropathol. 2017 Apr;133(4):517-533. doi: 10.1007/s00401-016-1656-8. Epub 2016 Dec 23.

Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy.

Author information

1
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.
2
INSERM U964, 67404, Illkirch, France.
3
CNRS, UMR7104, 67404, Illkirch, France.
4
Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404, Illkirch, France.
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.
6
Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
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.
8
Department of Anesthesia, Universitätsspital Basel, 4031, Basel, Switzerland.
9
Department of Biomedizin, Universitätsspital Basel, 4031, Basel, Switzerland.
10
Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
11
Departments of Pediatrics and Neurology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, 90048, USA.
12
The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, 90048, USA.
13
Assistance Publique des Hôpitaux de Paris (AP-HP), Service de Pédiatrie, Hôpital Raymond Poincaré, Hôpitaux Universitaires Paris-Ile-de-France Ouest, Garches, France.
14
Centre de Référence de Maladies Neuromusculaires Garches-Necker-Mondor-Hendaye (GNMH), Garches, France.
15
Réseau National Français de la Filière Neuromusculaire (FILNEMUS), Garches, France.
16
Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
17
Consultant-Neuropathology Department, National Pediatric Hospital J-P-Garrahan and Institute for Neurological Research-FLENI, Buenos Aires, Argentina.
18
Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
19
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.
20
Division of Neurology, Children's National Health System, Washington, DC, 20010, USA.
21
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
22
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
23
Laboratoire de Diagnostic Génétique, Faculté de Médecine, Nouvel Hôpital Civil, 67000, Strasbourg, France.
24
Faculté de Médecine, ICube-UMR7357, CSTB Complex Systems and Translational Bioinformatics, 67000, Strasbourg, France.
25
Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
26
Centre de référence des maladies neuromusculaires Nantes/Angers, Service de Neurologie, CHU Angers, Angers, France.
27
Université de Versailles-St Quentin, U1179 UVSQ-INSERM, Montigny, France.
28
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France. jocelyn@igbmc.fr.
29
INSERM U964, 67404, Illkirch, France. jocelyn@igbmc.fr.
30
CNRS, UMR7104, 67404, Illkirch, France. jocelyn@igbmc.fr.
31
Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404, Illkirch, France. jocelyn@igbmc.fr.

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.

KEYWORDS:

Centronuclear myopathy; Congenital myopathy; Core myopathy; DHPR; Excitation–contraction coupling; Myotubular myopathy; Triad

PMID:
28012042
DOI:
10.1007/s00401-016-1656-8
[Indexed for MEDLINE]

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