Novel ryanodine receptor mutation that may cause malignant hyperthermia.

摘要

BACKGROUND: Malignant hyperthermia (MH) is a hypermetabolic condition caused by a genetic disposition leading to increased Ca release from the sarcoplasmic reticulum after exposure to triggering agents. In the authors' ongoing evaluation of patients undergoing MH testing in Austria, they detected a family with a new variant of the ryanodine receptor 1. Guidelines suggest that genetic tests are possible only for individuals from families in which the mutations are known. The aim of this study was to provide functional data that establish a potential link between this new variant and susceptibility to MH, and thus enable application in genetic tests. METHODS: Messenger RNA was isolated from skeletal muscle cells grown in culture and used for synthesis of complementary DNA, which served as a template for 23 polymerase chain reactions. The sequences of all reaction products were analyzed. Functional studies in differentiated muscle cells included the Ca releasing activity of caffeine and 4-chloro-m-cresol.The authors measured the intracellular Ca concentration and, in combined patch clamp-Ca detection experiments, the voltage dependence of the Ca release. RESULTS: In a single family, the authors found a transition from a highly conserved thymine to cysteine at position 11953, leading to the exchange of tryptophan to arginine at position 3985. This variant was absent in 100 MH-nonsusceptible individuals. Functionally, cells carrying this variant were more sensitive to caffeine and 4-chloro-m-cresol than wild-type cells and showed a shift in the voltage-dependent Ca release to more negative potentials. CONCLUSION: These data document a role of the new W3985R variant in MH susceptibility.