Mitochondrial encephalopathy Due to a Novel Pathogenic Mitochondrial tRNA(Gln) m.4349C>T Variant

OBJECTIVE: Mitochondrial diseases are a group of genetic diseases caused by mutations in mitochondrial DNA and nuclear DNA, among which, mutations in mitochondrial tRNA genes possessing prominent status. In most of the cases, however, the detailed molecular pathogenesis of these tRNA gene mutations remains unclear. METHODS: We performed the clinical emulation, muscle histochemistry, northern blotting analysis of tRNA levels, biochemical measurement of respiratory chain complex activities and mitochondrial respirations in muscle tissue and cybrid cells. RESULTS: We found a novel m.4349C>T mutation in mitochondrial tRNA(Gln) gene in a patient present with encephalopathy, epilepsy, and deafness. We demonstrated molecular pathomechanisms of this mutation. This mutation firstly disturbed the translation machinery of mitochondrial tRNA(Gln)and impaired mitochondrial respiratory chain complex activities, followed by remarkable mitochondrial dysfunction and ROS production. Interpretation. This study illustrated the pathogenicity of a novel m.4349C>T mutation and provided a better understanding of the phenotype associated with mutations in mitochondrial tRNA(Gln) gene.