A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal Ca 2+ release channel function and severe central core disease

• DOI: 10.1073/pnas.96.7.4164
• Publication Date: 2002-07-26T14:32:33Z
• Authors: Patrick J. Lynch; Jiefei Tong; Mary Lehane; Alejandro Mallet; Linda Giblin; James J. A. Heffron; Pat Vaughan; Gildardo Zafra; David H. MacLennan; Tommie V. McCarthy
• Keywords: Central core disease; Compound heterozygosity

Central core disease is a rare, nonprogressive myopathy that characterized by hypotonia and proximal muscle weakness. In large Mexican kindred with an unusually severe highly penetrant form of the disorder, DNA sequencing identified I4898T mutation in C-terminal transmembrane/luminal region RyR1 protein constitutes skeletal ryanodine receptor. All previously reported RYR1 mutations are located either cytoplasmic N terminus or central 5,038-aa protein. The was introduced into rabbit cDNA expressed HEK-293 cells. response mutant Ca 2+ channel to agonists halothane caffeine photometry assay completely abolished. Coexpression normal cDNAs 1:1 ratio, however, produced channels sensitivities, but maximal levels release were reduced 67%. [ 3 H]Ryanodine binding indicated heterozygous activated concentrations 4-fold lower than normal. Single-cell analysis cotransfected cells showed significantly increased resting level luminal level. These data indicative leaky channel, possibly caused reduction concentration required for activation. Comparison two other coexpressed mutant/normal suggests produces one most abnormal yet investigated, this abnormality reflected phenotype affected individuals.