Molecular Characterization of Two Hypertension Pedigrees Carrying Mitochondrial tRNAGln 4386T>C Mutation

Abstract Introduction: The aim of this study was to explore the relationships between mitochondrial tRNA (mt-tRNA) mutations and essential hypertension (EH), and providing the valuable information for molecular diagnosis of EH. Methods: We reported here clinical, genetic and molecular characterizations of two Han Chinese pedigrees with maternally inherited EH. We first amplified the mitochondrial genomes of the matrilineal relatives with EH, furthermore, Sanger sequencing was used to screen mitochondrial DNA (mtDNA) mutations. Phylogenetic conservation, mt-tRNA structural analyses, as well as mitochondrial functional evaluations were performed to assess the potential pathogenicity of mtDNA mutations. Results: EH-1 and EH-2 pedigrees exhibited typically maternal transmission; analysis of mitochondrial genomes revealed the co-existence of tRNAGln 4386T>C mutation in both families. Moreover, members of EH-2 pedigree carried the tRNAAla 5601C>T mutation. The m.4386T>C and m.5601C>T mutations were very conserved and implicated to have impact on mitochondrial functions. Compared with the control cells and cells with only the m.4386T>C mutation, cells carrying both m.4386T>C and m.5601C>T mutations exhibited much lower levels of ATP, membrane potential and mtDNA copy number, whereas reactive oxygen species increased significantly. Thus, the m.5601C>T and m.4386T>C mutations caused mitochondrial dysfunctions and involved in EH progression. Conclusion: The m.5601C>T may be a secondary variant that increase the penetrance and expressivity of hypertension-associated tRNAGln 4386T>C mutation.