Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy

Schartner, Vanessa and Romero, Norma B. and Donkervoort, Sandra and Treves, Susan and Munot, Pinki and Pierson, Tyler Mark and Dabaj, Ivana and Malfatti, Edoardo and Zaharieva, Irina T. and Zorzato, Francesco and Abath Neto, Osorio and Brochier, Guy and Lornage, Xavière and Eymard, Bruno and Taratuto, Ana Lia and Bohm, Johann and Gonorazky, Hernan and Ramos-Platt, Leigh and Feng, Lucy and Phadke, Rahul and Bharucha-Goebel, Diana X. and Sumner, Charlotte Jane and Bui, Mai Thao and Lacene, Emmanuelle and Beuvin, Maud and Labasse, Clémence and Dondaine, Nicolas and Schneider, Raphael and Thompson, Julie and Boland, A. and Deleuze, Jean-François and Matthews, Emma and Pakleza, Aleksandra Nadaj and Sewry, Caroline A. and Biancalana, Valérie and Quijano-Roy, Susana and Muntoni, Francesco and Fardeau, Michel and Bönnemann, Carsten G. and Laporte, Jocelyn. (2017) Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy. Acta neuropathologica, 133 (4). pp. 517-533.

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Official URL: https://edoc.unibas.ch/62497/

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Perioperative Patient Safety (Girard/Treves)
UniBasel Contributors:Treves, Susan
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:04 Aug 2020 14:29
Deposited On:04 Aug 2020 14:29

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