The Mitochondrial tRNA^Asp T7561C, tRNA^His C12153T, and A12172G Mutations May Be Associated with Essential Hypertension in a Han Chinese Pedigree

Abstract

Objectives: Mutations in mitochondrial tRNA (mt-tRNA) are the important causes for maternally inherited hypertension, however, the pathophysiology of mt-tRNA mutations in clinical expression of hypertension remains poorly understood. Material and Methods: In this study, we report the molecular features of a Han Chinese pedigree with maternally transmitted essential hypertension. The entire mitochondrial genomes are PCR amplified and sequenced, Moreover, phylogenetic analysis, haplogroup analysis, as well as pathogenicity scoring system are used to assess the potential roles for mtDNA mutations. Results: Strikingly, among ten matrilineal relatives, three of them suffer from variable degree of hypertension at different age at onset. Sequence analysis of the complete mitochondrial genomes suggests the presence of three possible pathogenic mtDNA mutations: tRNAAsp T7561C, tRNAHis C12153T and A12172G, together with a set of variants belonging to East Asian mitochondrial haplogroup M7a. Interestingly, the T7561C mutation occurs at position 44 in the variable region of tRNAAsp, while the C12153T and A12172G mutations are localized at extremely conserved nucleotides in the D-arm and anticodon stem of tRNAHis gene, respectively, which are critical for tRNA steady-state level and function. Conclusions: Mitochondrial T7561C, C12153T and A12172G mutations may lead to the failure in tRNAs metabolism, and cause mitochondrial dysfunction that is responsible for hypertension. However, the homoplasmy form of mt-tRNA mutations, incomplete penetrance of hypertension suggest that T7561C, C12153T and A12172G mutations are insufficient to produce the clinical phenotype, hence, other risk factors such as environmental factors, nuclear genes and epigenetic modifications may contribute to the phenotypic manifestation of maternally inherited hypertension in this Chinese pedigree.

Maternal Ezh1/2 deficiency impairs the function of mitochondria in mouse oocytes and early embryos

“…mtDNA has no histone protein and is easily damaged (Scheibye‐Knudsen et al, 2015; Stewart & Chinnery, 2015). Metabolic abnormalities, poisons, and oxidative stress can lead to mtDNA damage and produce offspring diseases (such as hypertension, cardiovascular disease) (Fu et al, 2022; Holt et al, 1988; Shu et al, 2021; Wallace et al, 1988). At the same time, mtDNA damage may also induce epigenetic modifications (Sharma et al, 2019).…”

Mutational Screening for Mitochondrial tRNA Genes in 100 Women with Pre-Eclampsia

“…In fact, most mt-tRNAs from all domains of life had a highly conserved cloverleaf structure, consisting of an acceptor arm, D-arm, anticodon stem, variable region, and T-loop, with an average length of 73 nucleotides. In addition, the secondary structure of mt-tRNAs contains a significant amount of unstable nucleotide pairs, such as non-Watson-Crick pairs and A-U pairs, and these features mean that mt-tRNAs had lower thermal stability and were more susceptible to mutation than nuclear-encoded tRNAs [14, 15]. mt-tRNA point mutations typically caused a loss of mt-tRNA stability, leading to defective mitochondrial translation and a combined respiratory chain deficiency.…”