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

Objectives: To investigate the role of m.4435A>G and c.572G>T (p.G191V) mutations in the development of essential hypertension.

Methods: A hypertensive patient with m.4435A>G and p.G191V mutations was identified from previously collected mitochondrial genome and exon sequencing data. Clinical data were collected, and a molecular genetic study was conducted in the proband and his family members. Peripheral venous blood was collected, and immortalized lymphocyte lines constructed. The mitochondrial transfer RNA (tRNA), mitochondrial protein, adenosine triphosphate (ATP), mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) in the constructed lymphocyte cell lines were measured.

Results: Mitochondrial genome sequencing 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 may influence the anticodon ring structure. Compared with the control group, the cell lines carrying m.4435A>G and p.G191V mutations had decreased mitochondrial tRNA homeostasis, mitochondrial protein expression, ATP production and MMP levels, as well as increased ROS levels (all <0.05).

Conclusions: The p.G191V mutation aggravates the changes in mitochondrial translation and mitochondrial function caused by m.4435A>G through affecting the steady-state level of mitochondrial tRNA and further leads to cell dysfunction, indicating that 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.