Molecular characterization of two Chinese pedigrees with maternally inherited hypertension

BACKGROUND Mutations in mitochondrial tRNA (mt-tRNA) genes are associated with hypertension, although their pathogenic mechanisms remain poorly understood. METHODS In the present study, two Han Chinese families with maternally transmitted hypertension were interviewed. The mtDNA mutations of matrilineal relatives were screened by polymerase chain reaction-Sanger sequencing. Mitochondrial ATP, membrane potential and reactive oxygen species (ROS) were also analyzed in polymononuclear leukocytes carrying these mt-tRNA mutations. Additionally, the levels of oxidative stress-related biomarkers [malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and 8-hydroxy-2-deoxyguanosine (8-OHdG)] were analyzed. RESULTS Nine of 13 adult matrilineal relatives of these pedigrees exhibited a wide range of severity of hypertension. The age at onset of hypertension was 30-62 years (average 46 years). Mutational screening of mitochondrial genomes revealed tRNAArg T10410C and T10454C mutations. Indeed, the m.T10454C and m.T10410C mutations occurred at conserved bases of TΨC-loop and acceptor arm of tRNAArg (positions 55 and 6), which are critical for tRNAArg post-transcriptional modification. Thus, the defects in tRNA modification may cause failure in tRNA metabolism, impairing mitochondrial translation. Biochemical analysis revealed that m.T10454C or m.T10410C mutation significantly reduced mitochondrial ATP and membrane potential and also increased ROS production in mutant cell lines (all p < 0.05). In addition, the levels of MDA and 8-OHdG in hypertensive patients markedly increased, whereas those of SOD and GSH-Px decreased (all p < 0.05). CONCLUSIONS These findings demonstrate that m.T10410C and m.T10454C mutations affect the structure and function of tRNAArg and consequently alter mitochondrial function and lead to oxidative stress, which are involved in the pathogenesis of maternally inherited hypertension.