Clinical and genetic analysis of essential hypertension with mitochondrial tRNAMet 4435A>G and YARS2 mutation.

Abstract

To investigate the role of m.4435A>G and YARS2 c.572G>T (p.G191V) mutations in the development of essential hypertension. A hypertensive patient with m.4435A>G and YARS2 p.G191V mutations was identified from the mitochondrial genome and exon sequencing data previously collected. Clinical data were collected, and the molecular genetic study was conducted in the proband and his family members. Peripheral venous blood was collected, and immortalized lymphocyte lines were constructed. The mitochondrial tRNA, mitochondrial protein, ATP, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) in the constructed lymphocyte cell lines were detected. Mitochondrial genome sequencing results showed that all maternal members carried a highly conserved m.4435A>G mutation. The m.4435A>G mutation might affect the secondary structure and folding free energy of mitochondrial tRNA and change its stability, which would affect the anticodon ring structure. Compared with the control group, the cell lines carrying m.4435A>G and YARS2 p.G191V mutations had decreased mitochondrial tRNA homeostasis, partial mitochondrial protein expression, ATP production, and MMP levels, and increased ROS levels. The differences were statistically significant (P<0.05). The YARS2 p.G191V mutation aggravates the changes in mitochondrial translation and mitochondrial function caused by m.4435A>G by affecting the steady-state level of mitochondrial tRNA and further leads to cell dysfunction, indicating that YARS2 p.G191V and m.4435A>G mutations have a synergistic effect in this family and jointly participate in the occurrence and development of essential hypertension.