Screening of Tissue from Malignant Hyperthermia–susceptible Patients Reveals Novel Genetic Mutations

Abstract

Screening of Tissue from Malignant Hyperthermia–susceptible Patients Reveals Novel Genetic Mutations. Sambuughin et al. (page 594)More than 20 ryanodine receptor 1 (RyR1) mutations have been identified in families with an inherited susceptibility to malignant hyperthermia (MH). Sambuughin et al. obtained skeletal muscle samples from 73 unrelated people with diagnoses of MH susceptibility by using the caffeine–halothane contracture test of the North American Malignant Hyperthermia Group. The patients had been referred for the test because of either a positive family history of MH or development of signs of MH during anesthesia.The muscle samples were collected during a period of 3 yr and were stored at −70°C. Genomic DNA was extracted from stored muscle tissue or peripheral blood and was amplified using standard polymerase chain reaction–based restriction fragment length polymorphism, single-strand conformation polymorphism, and sequencing analysis. Most of the known RyR1 mutations were analyzed using the restriction fragment length polymorphism method, whereas new mutations were searched by single-strand conformation polymorphism in exons 12, 15, 39, 40, 44, 45, and 46 of the gene. Seven known RyR1 mutations were detected at frequencies ranging from 1.4% to 5.5%. The research team also detected three novel amino acid substitutions, at frequencies of 1.4% each. All 10 mutations were in 16 unrelated individuals and account for 21.9% of the screened North American MH-susceptible population. Statistical correlation between caffeine–halothane contracture test phenotypes and RyR1 was not studied because of the small number of subjects carrying the same mutation and lack of family members for the study. The frequency and distribution of RyR1 gene mutations detected in this North American MH-susceptible population were different from those previously identified in Western Europe. Larger-scale studies are needed, say the authors, to assess the type and frequency of mutations in RyR1 associated with MH in the North American population.