Identification of G7304A Mutation in the Ryanodine Receptor Type 1 Gene in a Patient with Malignant Hyperthermia and an Extended Pedigree Study in a Korean Malignant Hyperthermia Family

Abstract

Background: Malignant hyperthermia (MH) is a disorder of the skeletal muscle manifested as a life threatening hypermetabolic crisis in susceptible individuals following exposure to inhalation anesthetics and depolarizing muscle relaxants. MH susceptibility (MHS) is inherited as an autosomal dominant trait and mutations in the gene encoding skeletal muscle ryanodine receptor (RYR1) are considered a common cause of the disorder. To date, more than 25 RYR1 mutations have been reported in families from Europe and North America. In Korea, however, little is known about the mutations in this candidate gene. Methods: For the analysis of novel or previously published known RYR1 mutations in 13 exons of the RYR1 gene, PCR amplification and direct sequencing were performed in the proband. After identification of RYR1 mutation in the proband, we performed an extended pedigree study with informed consent from 160 members of a Korean MH family. DNA from 160 members of this family was screened for the presence or absence of RYR1 mutation identified in the proband. Results: We identified a heterozygous G7304A mutation (Arg2435His) in exon 45 of the RYR1 gene in the proband. Six members of the family suffered fatal MH reaction and died. Two members including this proband had a fulminant MH episodes but survived. Two members of the family had presented with severe muscle hypotonia. PCR amplification for the screening of the site yields a fragment of 256 base pair (bp), which is fully cleaved into two fragments of 169 bp and 87 bp by Hga1 in normal individuals and 50% cleaved in individuals with a heterozygous mutation. We found the heterozygous G7304A mutation in 30 individuals from the 160 family members. Conclusions: This result is the first report to identify the mutation of RYR1 in patients with malignant hyperthermia in Korea. Further larger scale studies will provide important data regarding the frequency of occurrence of the RYR1 mutations in Korea and insight into the practicality of genetic screening relative to diagnosis of MHS and prevention of MH episodes and MH-related problems.