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

Abstract

<b><i>Objectives:</i></b> 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. <b><i>Material and Methods:</i></b> 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. <b><i>Results:</i></b> Strikingly, among 10 matrilineal relatives, 3 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: tRNA^Asp T7561C, tRNA^His 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 tRNA^Asp, while the C12153T and A12172G mutations are localized at extremely conserved nucleotides in the D-arm and anticodon stem of tRNA^His gene, respectively, which are critical for tRNA steady-state level and function. <b><i>Conclusions:</i></b> 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 suggests 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.