THE SUBSTITUTION OF ARG FOR GLY(2433) IN THE HUMAN SKELETAL-MUSCLE RYANODINE RECEPTOR IS ASSOCIATED WITH MALIGNANT HYPERTHERMIA

Single strand conformational polymorphism analysis was used to screen exons 43 and 44 in the skeletal muscle ryanodine receptor gene from 17 positively diagnosed members of families in which chromosome 19-linke d malignant hyperthermia (MH) was segregating. A polymorphism in two u nrelated individuals was found to result from the substitution of A fo r G7297, leading to the substitution of Arg for Gly(2433). This mutati on is adjacent to a mutation (Arg(2434) to His) previously linked to M H and central core disease (Y.Zhang et al., Nature Genet. 1993, 5, 46 - 50). Subsequent screening showed the presence of the mutation in fou r of 106 MH families tested and its absence from about 1000 other chro mosomes. The mutation was present in all six individuals in four famil ies who had had an MH reaction, in two obligate carriers and in 10 ind ividuals diagnosed as MH susceptible by the caffeine/halothane contrac ture test (CHCT). The mutation was present in an individual with a nor mal response to the CHCT and was absent in three individuals with a po sitive CHCT response. These discrepancies would be consistent with ina ccuracies in the CHCT and/or with segregation of a second MH allele wi thin two of the four affected families.