Acta Neuropathologica

, Volume 124, Issue 4, pp 575–581

Samaritan myopathy, an ultimately benign congenital myopathy, is caused by a RYR1 mutation

  • Johann Böhm
  • Esther Leshinsky-Silver
  • Stéphane Vassilopoulos
  • Stéphanie Le Gras
  • Tally Lerman-Sagie
  • Mira Ginzberg
  • Bernard Jost
  • Dorit Lev
  • Jocelyn Laporte
Original Paper

DOI: 10.1007/s00401-012-1007-3

Cite this article as:
Böhm, J., Leshinsky-Silver, E., Vassilopoulos, S. et al. Acta Neuropathol (2012) 124: 575. doi:10.1007/s00401-012-1007-3

Abstract

Congenital myopathies describe a group of inherited muscle disorders with neonatal or infantile onset typically associated with muscle weakness, respiratory involvement and delayed motor milestones. We previously reported a novel congenital myopathy in an inbred Samaritan family. All patients displayed severe neonatal hypotonia and respiratory distress, and unlike other congenital myopathies, a constantly improving health status. As clinical and pathological data did not point to preferential candidate genes, we performed exome sequencing complemented by linkage analysis to identify the mutation causing the benign Samaritan congenital myopathy. We identified the homozygous p.Tyr1088Cys mutation in RYR1, encoding the skeletal muscle ryanodine receptor. This sarcoplasmic reticulum calcium channel is a key regulator of excitation–contraction coupling (ECC). Western blot and immunohistofluorescence revealed a significant decrease of the RYR1 protein level and an abnormal organization of skeletal muscle triad markers as caveolin-3, dysferlin and amphiphysin 2. RYR1 mutations are associated with different myopathies and malignant hyperthermia susceptibility. The index patient had mild hyperthermia following anesthesia, indicating that the inbred Samaritan population might be a risk group for this disorder. Our results suggest an aberrant ECC as the primary cause of this disease, and broaden the clinical consequences of RYR1 defects.

Keywords

Congenital myopathy Samaritan RYR1 Exome sequencing Malignant hyperthermia 

Supplementary material

401_2012_1007_MOESM1_ESM.doc (76 kb)
Supplementary material 1 (DOC 77 kb)
401_2012_1007_MOESM2_ESM.tif (7.5 mb)
Supplementary material 2 (TIFF 7703 kb)

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Johann Böhm
    • 1
    • 2
    • 3
    • 4
    • 5
  • Esther Leshinsky-Silver
    • 6
    • 7
    • 8
  • Stéphane Vassilopoulos
    • 9
  • Stéphanie Le Gras
    • 10
  • Tally Lerman-Sagie
    • 7
    • 8
  • Mira Ginzberg
    • 7
  • Bernard Jost
    • 10
  • Dorit Lev
    • 7
    • 8
    • 11
  • Jocelyn Laporte
    • 1
    • 2
    • 3
    • 4
    • 5
  1. 1.Department of Translational Medecine and NeurogeneticsIGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire)IllkirchFrance
  2. 2.InsermIllkirchFrance
  3. 3.CNRSIllkirchFrance
  4. 4.Université de StrasbourgIllkirchFrance
  5. 5.Chaire de Génétique HumaineCollège de FranceIllkirchFrance
  6. 6.Molecular Genetics LaboratoryWolfson Medical CenterHolonIsrael
  7. 7.Metabolic Neurogenetic ClinicWolfson Medical CenterHolonIsrael
  8. 8.Sackler School of MedicineTel-Aviv UniversityTel-AvivIsrael
  9. 9.Université Pierre et Marie Curie, University Paris 06, UM76, Institut de Myologie, INSERM U974 and CNRS UMR7215ParisFrance
  10. 10.DNA Microarrays and Sequencing PlatformIGBMCIllkirchFrance
  11. 11.Institute of Medical GeneticsWolfson Medical CenterHolonIsrael

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