Schartner, V;
Romero, NB;
Donkervoort, S;
Treves, S;
Munot, P;
Pierson, TM;
Dabaj, I;
... Laporte, J; + view all
(2016)
Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy.
Acta Neuropathologica
, 133
(4)
pp. 517-533.
10.1007/s00401-016-1656-8.
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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.
| Type: | Article |
|---|---|
| Title: | Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1007/s00401-016-1656-8 |
| Publisher version: | https://doi.org/10.1007/s00401-016-1656-8 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences, Pathology, Neurosciences & Neurology, DHPR, Congenital myopathy, Excitation-contraction coupling, Triad, Centronuclear myopathy, Core myopathy, Myotubular myopathy, HYPOKALEMIC PERIODIC PARALYSIS, INTRACELLULAR CALCIUM HOMEOSTASIS, MUSCULAR DYSGENESIS MDG, II-III-LOOP, SKELETAL-MUSCLE, CENTRONUCLEAR MYOPATHY, RELEASE CHANNEL, MUTATIONS, SUBUNIT, GENE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10051648 |
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