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 Phadke
  • Diana 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
Original Paper

DOI: 10.1007/s00401-016-1656-8

Cite this article as:
Schartner, V., Romero, N.B., Donkervoort, S. et al. Acta Neuropathol (2016). doi:10.1007/s00401-016-1656-8

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.

Keywords

DHPRCongenital myopathyExcitation–contraction couplingTriadCentronuclear myopathyCore myopathyMyotubular myopathy

Supplementary material

401_2016_1656_MOESM1_ESM.pdf (111.9 mb)
Supplementary material 1 (PDF 114621 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Vanessa Schartner
    • 1
    • 2
    • 3
    • 4
  • Norma B. Romero
    • 5
    • 6
  • Sandra Donkervoort
    • 7
  • Susan Treves
    • 8
    • 9
  • Pinki Munot
    • 10
  • Tyler Mark Pierson
    • 11
    • 12
  • Ivana Dabaj
    • 13
    • 14
    • 15
  • Edoardo Malfatti
    • 5
    • 6
  • Irina T. Zaharieva
    • 10
  • Francesco Zorzato
    • 8
    • 9
  • Osorio Abath Neto
    • 1
    • 7
  • Guy Brochier
    • 5
    • 6
  • Xavière Lornage
    • 1
    • 2
    • 3
    • 4
  • Bruno Eymard
    • 16
  • Ana Lía Taratuto
    • 17
  • Johann Böhm
    • 1
    • 2
    • 3
    • 4
  • Hernan Gonorazky
    • 18
  • Leigh Ramos-Platt
    • 19
  • Lucy Feng
    • 10
  • Rahul Phadke
    • 10
  • Diana X. Bharucha-Goebel
    • 7
    • 20
  • Charlotte Jane Sumner
    • 21
    • 22
  • Mai Thao Bui
    • 5
    • 6
  • Emmanuelle Lacene
    • 5
    • 6
  • Maud Beuvin
    • 5
    • 6
  • Clémence Labasse
    • 5
    • 6
  • Nicolas Dondaine
    • 26
  • Raphael Schneider
    • 1
    • 2
    • 3
    • 4
    • 23
  • Julie Thompson
    • 23
  • Anne Boland
    • 24
  • Jean-François Deleuze
    • 24
  • Emma Matthews
    • 10
  • Aleksandra Nadaj Pakleza
    • 25
  • Caroline A. Sewry
    • 10
  • Valérie Biancalana
    • 1
    • 2
    • 3
    • 4
    • 26
  • Susana Quijano-Roy
    • 13
    • 14
    • 15
    • 27
  • Francesco Muntoni
    • 10
  • Michel Fardeau
    • 5
    • 6
  • Carsten G. Bönnemann
    • 7
  • Jocelyn Laporte
    • 1
    • 2
    • 3
    • 4
  1. 1.Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)IllkirchFrance
  2. 2.INSERM U964IllkirchFrance
  3. 3.CNRS, UMR7104IllkirchFrance
  4. 4.Fédération de Médecine Translationnelle de Strasbourg (FMTS)Université de StrasbourgIllkirchFrance
  5. 5.Université Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in MyologyGH Pitié-SalpêtrièreParisFrance
  6. 6.Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-SalpêtrièreAssistance Publique-Hôpitaux de ParisParisFrance
  7. 7.Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesdaUSA
  8. 8.Department of AnesthesiaUniversitätsspital BaselBaselSwitzerland
  9. 9.Department of BiomedizinUniversitätsspital BaselBaselSwitzerland
  10. 10.Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular DiseasesUCL Great Ormond Street Institute of Child HealthLondonUK
  11. 11.Departments of Pediatrics and NeurologyCedars-Sinai Medical CenterLos AngelesUSA
  12. 12.The Board of Governors Regenerative Medicine InstituteCedars-Sinai Medical CenterLos AngelesUSA
  13. 13.Assistance Publique des Hôpitaux de Paris (AP-HP), Service de Pédiatrie, Hôpital Raymond PoincaréHôpitaux Universitaires Paris-Ile-de-France OuestGarchesFrance
  14. 14.Centre de Référence de Maladies Neuromusculaires Garches-Necker-Mondor-Hendaye (GNMH)GarchesFrance
  15. 15.Réseau National Français de la Filière Neuromusculaire (FILNEMUS)GarchesFrance
  16. 16.Centre de Référence de Pathologie Neuromusculaire Paris-EstGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  17. 17.Consultant-Neuropathology DepartmentNational Pediatric Hospital J-P-Garrahan and Institute for Neurological Research-FLENIBuenos AiresArgentina
  18. 18.Division of Neurology, Department of Pediatrics, The Hospital for Sick ChildrenUniversity of TorontoTorontoCanada
  19. 19.Division of Neurology at Children’s Hospital of Los Angeles, Department of Pediatrics, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  20. 20.Division of NeurologyChildren’s National Health SystemWashingtonUSA
  21. 21.Department of NeurologyJohns Hopkins University School of MedicineBaltimoreUSA
  22. 22.Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA
  23. 23.Faculté de MédecineICube-UMR7357, CSTB Complex Systems and Translational BioinformaticsStrasbourgFrance
  24. 24.Centre National de Génotypage, Institut de Génomique, CEAEvryFrance
  25. 25.Centre de référence des maladies neuromusculaires Nantes/Angers, Service de NeurologieCHU AngersAngersFrance
  26. 26.Laboratoire de Diagnostic Génétique, Faculté de MédecineNouvel Hôpital CivilStrasbourgFrance
  27. 27.Université de Versailles-St Quentin, U1179 UVSQ-INSERMMontignyFrance