title: A truncation in the RYR1 gene associated with central core lesions in skeletal muscle fibres.
abstract: 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.
authors.affiliation: Molecular Medicine Section, Department of Neuroscience, University of Siena, Siena 53100, Italy. v.sorrentino@unisi.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rossi
authors.forename: Patrick
authors.initials: P
authors.lastname: De Smet
authors.forename: Alla
authors.initials: A
authors.lastname: Lyfenko
authors.forename: Lucia
authors.initials: L
authors.lastname: Galli
authors.forename: Stefania
authors.initials: S
authors.lastname: Lorenzini
authors.forename: Daniela
authors.initials: D
authors.lastname: Franci
authors.forename: Francesco
authors.initials: F
authors.lastname: Petrioli
authors.forename: Alfredo
authors.initials: A
authors.lastname: Orrico
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tegazzin
authors.forename: Robert
authors.initials: R
authors.lastname: Dirksen
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Sorrentino
mesh_terms: D000368:Aged; D000818:Animals; D001706:Biopsy; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D005091:Exons; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D006801:Humans; D007668:Kidney; D007962:Leukocytes / Q000502:physiology; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000473:pathology* / Q000502:physiology; D018482:Muscle, Skeletal / Q000473:pathology* / Q000503:physiopathology; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D017384:Sequence Deletion
chemical_list: D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D004247:DNA; D002118:Calcium