A truncation in the RYR1 gene associated with central core lesions in skeletal muscle fibres.

Daniela Rossi, Patrick De Smet, Alla Lyfenko, Lucia Galli, Stefania Lorenzini, Daniela Franci, Francesco Petrioli, Alfredo Orrico, Corrado Angelini, Vincenzo Tegazzin, Robert Dirksen, Vincenzo Sorrentino

Research output: Contribution to journalArticlepeer-review


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 RyR1(R4836fsX4838) 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.

Original languageEnglish
JournalJournal of Medical Genetics
Issue number2
Publication statusPublished - Feb 2007

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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