Mitochondrial tRNA^Ala C5601T mutation may modulate the clinical expression of tRNA^Met A4435G mutation in a Han Chinese family with hypertension

Abstract

Mutations in mitochondrial DNA, especially in mitochondrial tRNA (mt-tRNA) genes, are the important causes for maternally inherited hypertension. In this study, we reported the clinical, genetic, and molecular characterization of a Han Chinese family with hypertension. Most strikingly, this family exhibited a high penetrance and expressivity of hypertension. Sequence analysis of the complete mt-tRNA genes showed the presence of tRNA A4435G and tRNA C5601T mutations. The A4435G had already been reported as a pathogenic mutation associated with hypertension; in addition, the C5601T mutation, which was located at the highly conserved nucleotide of T arm of tRNA, created a novel Watson-Crick base pairing and may result in failure of tRNA metabolism. Moreover, bioinformatics analysis indicated that the C5601T mutation altered the secondary structure of tRNA. Thus, the mitochondrial dysfunction, caused by the A4435G mutation, may be worsened by the C5601T mutation. Taken together, our data indicated that the co-occurrence of the A4435G and C5601T mutations may account for the high penetrance and expressivity of hypertension in this family. Therefore, our study provided novel insight into the pathophysiology of maternally inherited hypertension.

Mitochondrial DNA 7908–8816 region mutations in maternally inherited essential hypertensive subjects in China

“…Mutations in protein-encoding genes are frequently associated with ATPase dysfunction [ 26 ]. Failure in tRNA metabolism will lead to the deficiency of mitochondrial protein synthesis [ 27 ]. Defects in mitochondrial translation consequently result in a respiratory phenotype and a decrease in ATP production,may reduce the production of ROS,and subsequently have the potential role to affect the course of hypertension [ 28 ].…”

Mitochondrial tRNAAla 5601C>T variant may affect the clinical expression of the LHON‑related ND4 11778G>A mutation in a family

“…Bioinformatics analysis revealed that the m.5601C>T variant created a novel Watson-Crick base-pairing (55T-59C). The tRNA Ala m.5601C>T variant has previously been associated with maternally inherited hypertension and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (35,36). Therefore, the m.5601C>T may alter the secondary structure of tRNA Ala and impair the mt-tRNA metabolism and protein translation, and contribute to the LHON phenotype.…”

The mitochondrial tRNAAla 5587T>C and tRNALeu(CUN) 12280A>G mutations may be associated with hypertension in a Chinese family

“…To analysis the mutations/polymorphisms in mt-tRNA genes, the genomic DNA was extracted from the blood samples using the Puregene DNA Isolation kit (Gentra Systems, Inc., Minneapolis, MN, USA). The 22 mt-tRNA genes were polymerase chain reaction (PCR) amplified using 11 primers as described previously (7). The PCR products were purified and analyzed by direct sequencing in an ABI 3700 automated DNA sequencer (Applied Biosystems; Thermo Fisher Scientific, Inc., Waltham, MA, USA) using a Big Dye Terminator Cycle sequencing reaction kit version 3.1 (Applied Biosystems; Thermo Fisher Scientific, Inc.).…”

“…To assess the potential pathogenic roles of the tRNA Leu(CUN) 12280A>G and tRNA Ala 5587T>C mutations, the CIs of the mutations were evaluated using phylogenetic conservation analysis (7). The following species were selected for the phylogenetic conservation analysis: (17).…”

“…In fact, previous studies demonstrated that mitochondrial dysfunction caused by mitochondrial (mt)DNA mutations were important causes for hypertension (6). Several mitochondrial transfer (mt-t)RNA mutations have been reported to be associated with hypertension, these mutations include mt-tRNA Ala 5587T>C (thymine to cytosine) (7); mt-tRNA Gln 4375C>T (8), mt-tRNA Met 4435A>G (9) and mt-tRNA Leu(CUN) 12280A>G (adenine to guanine) (10). The authors of the current study noticed that these mutations may decrease the steady-state level of mt-tRNAs and subsequently cause the mitochondrial dysfunction that is responsible for hypertension.…”