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.