title: The Ile2453Thr mutation in the ryanodine receptor gene 1 is associated with facilitated calcium release from sarcoplasmic reticulum by 4-chloro-m-cresol in human myotubes.
abstract: Central core disease (CCD) is a congenital disorder of skeletal muscle that is characterised histologically by typical central cores in type 1 skeletal muscle fibres. This disease is associated with malignant hyperthermia susceptibility and has been linked to the gene of skeletal muscle ryanodine receptor RYR1. In this study, we present a family with the spontaneous occurrence of the RYR1 Ile2453Thr mutation. Affected individuals were diagnosed as susceptible to malignant hyperthermia in the in vitro contracture test (IVCT) and showed histological signs of CCD. Myotubes were derived from the index patient. The calcium homeostasis in response to the ryanodine receptor agonist 4-chloro-m-cresol (4CmC) was investigated by calcium imaging using the Ca(2+)-sensitive fluorescent probe FURA 2. In the myotubes derived from the mutation carrier, the EC(50) of 4CmC was reduced to 94 micro as compared to 201 microM in a control group of 16 individuals non-susceptible to malignant hyperthermia. In the myotubes of the non-affected family members, the EC(50) was found within the same range as that of the control group. The reduction of EC(50) indicates a facilitated calcium release from sarcoplasmic reticulum in the myotubes of the index patient suggesting that the RYR1 Ile2453Thr mutation is pathogenic for the malignant hyperthermia susceptibility and CCD of the two affected individuals.
authors.affiliation: Department of Anaesthesiology and Intensive Care, Leipzig University Hospital, Liebigstrasse 20a, 04103 Leipzig, Germany. wehm@medizin.uni-leipzig.de
authors.forename: Markus
authors.initials: M
authors.lastname: Wehner
authors.forename: Henrik
authors.initials: H
authors.lastname: Rueffert
authors.forename: Fritjoff
authors.initials: F
authors.lastname: Koenig
authors.forename: Claus Dieter
authors.initials: CD
authors.lastname: Meinecke
authors.forename: Derk
authors.initials: D
authors.lastname: Olthoff
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002118:Calcium / Q000378:metabolism*; D002648:Child; D003408:Cresols / Q000494:pharmacology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D020512:Myopathy, Central Core / Q000235:genetics*; D010375:Pedigree; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: D003408:Cresols; D019837:Ryanodine Receptor Calcium Release Channel; C006984:chlorocresol; D002118:Calcium