Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)517-533
Number of pages17
JournalActa neuropathologica
Issue number4
StatePublished - Apr 1 2017


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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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