Journal Article

Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy

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

2017

Overview

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 2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca 2+ 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 v 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 2+ 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.

• Publisher: Springer Berlin Heidelberg,Springer,Springer Nature B.V,Springer Verlag
• Subject: Adolescent / Adult / Biochemistry, Molecular Biology / Calcium - metabolism / Calcium Channels - genetics / Calcium Channels - metabolism / Cells, Cultured / Child / Cohort Studies / Congenital diseases / Family / Female / Genetic disorders / Humans / Hyperthermia / Life Sciences / Male / Medicine / Medicine & Public Health / Middle Aged / Muscle Cells - metabolism / Muscle Cells - pathology / Muscle contraction / Muscle, Skeletal - diagnostic imaging / Muscle, Skeletal - metabolism / Muscle, Skeletal - pathology / Musculoskeletal system / Mutation / Myotonia Congenita - diagnostic imaging / Myotonia Congenita - genetics / Myotonia Congenita - metabolism / Myotonia Congenita - pathology / Neuromuscular diseases / Neurosciences / Original Paper / Pathology / Phenotype / Sequence Homology, Amino Acid / Skeletal muscle / Young Adult