Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy

Vanessa Schartner, Norma B. Romero, Sandra Donkervoort, Susan Treves, Pinki Munot, Tyler Mark Pierson, Ivana Dabaj, Edoardo Malfatti, I. 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 Phadke & 20 others D. X. Bharucha-Goebel, Charlotte 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 journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1-17
Number of pages17
JournalActa Neuropathologica
DOIs
StateAccepted/In press - Dec 23 2016

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Myotonia Congenita
L-Type Calcium Channels
Sarcoplasmic Reticulum
Mutation
Skeletal Muscle
Hypokalemic Periodic Paralysis
Exome
Ophthalmoplegia
Malignant Hyperthermia
Muscles
Ryanodine Receptor Calcium Release Channel
Muscle Hypotonia
Skeletal Muscle Fibers
Muscle Contraction
Dilatation
Calcium
Phenotype
Biopsy
Therapeutics
Proteins

Keywords

  • 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

Cite this

Schartner, V., Romero, N. B., Donkervoort, S., Treves, S., Munot, P., Pierson, T. M., ... Laporte, J. (Accepted/In press). Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy. Acta Neuropathologica, 1-17. https://doi.org/10.1007/s00401-016-1656-8

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

In: Acta Neuropathologica, 23.12.2016, p. 1-17.

Research output: Contribution to journalArticle

Schartner, V, Romero, NB, Donkervoort, S, Treves, S, Munot, P, Pierson, TM, Dabaj, I, Malfatti, E, Zaharieva, IT, Zorzato, F, Abath Neto, O, Brochier, G, Lornage, X, Eymard, B, Taratuto, AL, Böhm, J, Gonorazky, H, Ramos-Platt, L, Feng, L, Phadke, R, Bharucha-Goebel, DX, Sumner, C, Bui, MT, Lacene, E, Beuvin, M, Labasse, C, Dondaine, N, Schneider, R, Thompson, J, Boland, A, Deleuze, JF, Matthews, E, Pakleza, AN, Sewry, CA, Biancalana, V, Quijano-Roy, S, Muntoni, F, Fardeau, M, Bönnemann, CG & Laporte, J 2016, 'Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy', Acta Neuropathologica, pp. 1-17. https://doi.org/10.1007/s00401-016-1656-8
Schartner V, Romero NB, Donkervoort S, Treves S, Munot P, Pierson TM et al. Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy. Acta Neuropathologica. 2016 Dec 23;1-17. https://doi.org/10.1007/s00401-016-1656-8
Schartner, Vanessa ; Romero, Norma B. ; Donkervoort, Sandra ; Treves, Susan ; Munot, Pinki ; Pierson, Tyler Mark ; Dabaj, Ivana ; Malfatti, Edoardo ; Zaharieva, I. T. ; Zorzato, Francesco ; Abath Neto, Osorio ; Brochier, Guy ; Lornage, Xavière ; Eymard, Bruno ; Taratuto, Ana Lía ; Böhm, Johann ; Gonorazky, Hernan ; Ramos-Platt, Leigh ; Feng, Lucy ; Phadke, Rahul ; Bharucha-Goebel, D. X. ; Sumner, Charlotte ; Bui, Mai Thao ; Lacene, Emmanuelle ; Beuvin, Maud ; Labasse, Clémence ; Dondaine, Nicolas ; Schneider, Raphael ; Thompson, Julie ; Boland, Anne ; Deleuze, Jean François ; Matthews, Emma ; Pakleza, Aleksandra Nadaj ; Sewry, Caroline A. ; Biancalana, Valérie ; Quijano-Roy, Susana ; Muntoni, Francesco ; Fardeau, Michel ; Bönnemann, Carsten G. ; Laporte, Jocelyn. / Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy. In: Acta Neuropathologica. 2016 ; pp. 1-17.
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AU - Schartner, Vanessa

AU - Romero, Norma B.

AU - Donkervoort, Sandra

AU - Treves, Susan

AU - Munot, Pinki

AU - Pierson, Tyler Mark

AU - Dabaj, Ivana

AU - Malfatti, Edoardo

AU - Zaharieva, I. T.

AU - Zorzato, Francesco

AU - Abath Neto, Osorio

AU - Brochier, Guy

AU - Lornage, Xavière

AU - Eymard, Bruno

AU - Taratuto, Ana Lía

AU - Böhm, Johann

AU - Gonorazky, Hernan

AU - Ramos-Platt, Leigh

AU - Feng, Lucy

AU - Phadke, Rahul

AU - Bharucha-Goebel, D. X.

AU - Sumner, Charlotte

AU - Bui, Mai Thao

AU - Lacene, Emmanuelle

AU - Beuvin, Maud

AU - Labasse, Clémence

AU - Dondaine, Nicolas

AU - Schneider, Raphael

AU - Thompson, Julie

AU - Boland, Anne

AU - Deleuze, Jean François

AU - Matthews, Emma

AU - Pakleza, Aleksandra Nadaj

AU - Sewry, Caroline A.

AU - Biancalana, Valérie

AU - Quijano-Roy, Susana

AU - Muntoni, Francesco

AU - Fardeau, Michel

AU - Bönnemann, Carsten G.

AU - Laporte, Jocelyn

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KW - Congenital myopathy

KW - Core myopathy

KW - DHPR

KW - Excitation–contraction coupling

KW - Myotubular myopathy

KW - Triad

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