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A truncation in the RYR1 gene associated with central core lesions in skeletal muscle fibres
  1. Daniela Rossi1,*,
  2. Patrick De Smet1,*,
  3. Alla Lyfenko2,
  4. Lucia Galli1,
  5. Stefania Lorenzini1,
  6. Daniela Franci1,
  7. Francesco Petrioli1,
  8. Alfredo Orrico1,
  9. Corrado Angelini3,
  10. Vincenzo Tegazzin4,
  11. Robert Dirksen2,
  12. Vincenzo Sorrentino1
  1. 1Molecular Medicine Section, Department of Neuroscience and Interuniversitary Institute of Myology, University of Siena, Siena, Italy
  2. 2Department of Pharmacology and Physiology, University of Rochester, Rochester, New York, USA
  3. 3Department of Neurosciences, S Antonio University Hospital, Padova, Italy
  4. 4Department of Anaesthesia, S Antonio University Hospital, Padova, Italy
  1. Correspondence to:
 Professor V Sorrentino
 Molecular Medicine Section, Department of Neuroscience, University of Siena, Siena 53100, Italy; v.sorrentino{at}


A novel single-nucleotide deletion in exon 100 of the RYR1 gene, corresponding to deletion of nucleotide 14 510 in the human RyR1 mRNA (c14510delA), was identified in a man with malignant hyperthermia and in his two daughters who were normal for malignant hyperthermia. This deletion results in a RyR1 protein lacking the last 202 amino acid residues. All three subjects heterozygotic for the mutated allele presented with a prevalence of type 1 fibres with central cores, although none experienced clinical signs of myopathy. Expression of the truncated protein resulted in non-functional RYR1 calcium release channels. Expression of wild-type and RyR1R4836fsX4838 proteins resulted in heterozygotic release channels with overall functional properties similar to those of wild-type RyR1 channels. Nevertheless, small differences in sensitivity to calcium and caffeine were observed in heterotetrameric channels, which also presented an altered assembly/stability in sucrose-gradient centrifugation analysis. Altogether, these data suggest that altered RYR1 tetramer assembly/stability coupled with subtle chronic changes in Ca2+ homoeostasis over the long term may contribute to the development of core lesions and incomplete malignant hyperthermia susceptibility penetrance in individuals carrying this novel RYR1 mutation.

  • CCD, central core disease
  • DHPR, dihydropyridine receptor
  • HEK, human embryonic kidney
  • IVCT, in vitro contracture test
  • MHS, malignant hyperthermia susceptibility

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  • * These authors contributed equally to this report.

  • Funding: This work was supported by a research grant from the National Institutes of Health (AR44657 to RTD) and by grants from Telethon (number GGP02168), EU grant (HPRN-CT-2002-00331) and from MIUR/PRIN 2003 to VS.

  • Competing interests: None declared.