Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in vitro contracture test

Malignant hyperthermia (MH) in man is an autosomal dominant disorder of ske letal muscle Ca2+-regulation, During anesthesia in predisposed individuals, it is triggered by volatile anesthetics and depolarizing muscle relaxants, In >50% of the families, MH susceptibility is linked to the gene encoding the skeletal muscle ryanodine receptor (RYR1), the calcium release channel of the sarcoplasmic reticulum, ion chromosome 19q12-13.2. To date, 21 RYR1 mutations have been identified in a number of pedigrees, Four of them are a lso associated with central core disease (CCD), a congenital myopathy, Scre ening for these 21 mutations in 105 MH families including 10 CCD families p henotyped by the in vitro contracture test (IVCT) according to the European protocol revealed the following approximate distribution: 9% Arg-614-Cys, 1% Arg-614-Leu, 1% Arg-2163-Cys, 1% Val-2168-Met, 3% Thr-2206-Met and 7% Gl y-2434-Arg. In one CCD family, the disease was caused by a recently reporte d MH mutation, Arg-2454-His. Two novel mutations, Thr-2206-Arg and Arg-2454 -Cys were detected, each in a single pedigree, In the 109 individuals of th e 25 families with RYR1 mutations cosegregation between genetic result and IVCT was almost perfect, only three genotypes were discordant with the IVCT phenotypes, suggesting a true sensitivity of 98.5% and a specificity of mi nimally 81.8% for this test, Screening of the transmembraneous region of RY R1 did not yield a new mutation confirming the cytosolic portion of the pro tein to be of main functional importance for disease pathogenesis.