Identification of new variants in MTRNR1 and MTRNR2 genes using whole mitochondrial genome sequencing in a Taiwanese family with MERRF (myoclonic epilepsy with ragged-red fibers) syndrome.

Mitochondrial encephalomyopathy is a multi-system disorder mostly caused by inborn errors of the oxidative phosphorylation (OXPHOS) system and usually manifested as complex neurological disorder and muscle weakness. Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is one of the major subtypes of mitochondrial disease associated with the m.8344A>G mutation in mitochondrial tRNALys gene. In addition to the symptoms in central nervous and muscle systems, a portion of the patients may develop hearing loss, which has been linked to the genetic mutations of mitochondrial DNA (mtDNA) especially in the mitochondrial ribosome RNA (rRNA) gene. Despite a great number of studies focusing on the consequences of mtDNA mutations, the mechanism of pathogenesis of these overt diseases has remained unclear, and there is no specific and effective treatment for MERRF syndromes. In this study, we developed a high-quality mtDNA sequencing method by next generation sequencing technology to search for the additional pathogenic variations of mtDNA from skin fibroblasts of four members in a Taiwanese family with MERRF syndrome. Through uncovering the signatures of all mtDNA variants in the MERRF family, we identified novel mtDNA variants in the genes encoding mitochondrial 12S and 16S rRNAs. The finding from this study will give us further insight into the molecular mechanisms driving the phenotypic variability and timing of onset of the MERRF syndrome.