Novel mutations identified in EIF2B5 gene in Kashmiri patients as susceptibility factor for multiple sclerosis.

White matter disease refers to a set of diseases that affect the white matter of the brain and all of which have different consequences on brain function. Most of the studies have shown that it results from the defects during protein synthesis, with the gene defects in EIF2B1–5, encoding the five subunits of eukaryotic translation initiation factor 2B (eIF2B) α, β, γ, δ and ε, respectively. eIF2B plays a crucial role in protein translation and its regulation under different conditions. The previous studies have shown that mutations in five subunits of eIF2B cause white matter disease of the brain and thus EIF2B is the main culprit in development of white matter disease. In this study, the mutational screening of EIF2B5 gene encoding eIF2Bε was performed for the first time in 12 Kashmiri patients, each having a unique white matter disease condition. We found two novel missense mutations in EIF2B5: c.580A>G, p.Thr194Ala and c.611C>T, p.Ala204Val among the patients with demyelinating disease (multiple sclerosis), but no mutation was found in other patients. In conclusion our study suggests involvement of the EIF2B5 gene in MS development, thus suggesting p.Thr194Ala to be a susceptibility factor for the development of multiple sclerosis.

Molecular Genetic Analysis of the Ryanodine Receptor Gene (RYR1) in Korean Malignant Hyperthermia Families / 대한진단검사의학회지

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.