[Molecular genetic analysis of the ryanodine receptor gene (RYR1) in Korean malignant hyperthermia families].

Background: Malignant hyperthermia (MH) is genetically heterogeneous, with mutations in the gene encoding the skeletal muscle ryanodine receptor (RYR1) at 19q13.1 accounting for up to 80% of the cases. However, the search for known and novel mutations in the RYR1 gene is hampered by the fact that the gene contains 106 exons. We aimed to analyze mutations from the entire RYR1 coding region in Korean MH families.

Methods: We investigated seven affected MH individuals and their family members. The entire RYR1 coding region from the genomic DNA was sequenced, and RYR1 haplotyping and mutational analysis were carried out.

Results: We identified nine different RYR1 mutations or variations from seven Korean MH families. Among these, five previously reported mutations (p.Gly248Arg, p.Arg2435His, p.Arg2458His, p.Arg2676Trp, and p.Leu4838Val) and four novel variations of unknown significance (p.Arg2508Cys, p.Met4022Val, p.Glu2669Lys, and p.Ala4295Val) were identified. In two families, two variations (R2676W & M4022V, R2435H & A4295V, respectively) were identified simultaneously. Four of the observed nine mutations or variations were located outside the hotspot region of RYR1 mutations.

Conclusions: These data indicate that RYR1 is a main candidate gene in Korean MH families, and that comprehensive screening of the entire coding sequence of the RYR1 gene is necessary for molecular genetic investigations in MH-susceptible individuals, owing to the presence of RYR1 mutations or variations outside of the hotspot region.