Dataset Information

Analysis of Mitochondrial Transfer RNA Mutations in Breast Cancer.

ABSTRACT: Damage of mitochondrial functions caused by mitochondrial DNA (mtDNA) pathogenic mutations had long been proposed to be involved in breast carcinogenesis. However, the detailed pathological mechanism remained deeply undetermined. In this case-control study, we screened the frequencies of mitochondrial tRNA (mt-tRNA) mutations in 80 breast cancer tissues and matched normal adjacent tissues. PCR and Sanger sequence revealed five possible pathogenic mutations: tRNA^Val G1606A, tRNA^Ile A4300G, tRNA^Ser(UCN) T7505C, tRNA^Glu A14693G and tRNA^Thr G15927A. We noticed that these mutations resided at extremely conserved positions of tRNAs and would affect tRNAs transcription or modifications. Furthermore, functional analysis suggested that patients with these mt-tRNA mutations exhibited much lower levels of mtDNA copy number and ATP, as compared with controls (p<0.05). Therefore, it can be speculated that these mutations may impair mitochondrial protein synthesis and oxidative phosphorylation (OXPHOS) complexes, which caused mitochondrial dysfunctions that were involved in the breast carcinogenesis. Taken together, our data indicated that mutations in mt-tRNA were the important contributors to breast cancer, and mutational analyses of mt-tRNA genes were critical for prevention of breast cancer.

SUBMITTER: Ding HJ

PROVIDER: S-EPMC10230833 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Analysis of Mitochondrial Transfer RNA Mutations in Breast Cancer.

Ding H J HJ Zhao Y P YP Jiang Z C ZC Zhou D T DT Zhu R R

Balkan journal of medical genetics : BJMG 20230502 2

Damage of mitochondrial functions caused by mitochondrial DNA (mtDNA) pathogenic mutations had long been proposed to be involved in breast carcinogenesis. However, the detailed pathological mechanism remained deeply undetermined. In this case-control study, we screened the frequencies of mitochondrial tRNA (mt-tRNA) mutations in 80 breast cancer tissues and matched normal adjacent tissues. PCR and Sanger sequence revealed five possible pathogenic mutations: tRNAVal G1606A, t ...[more]

PMID: 37265965

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Project description:IntroductionPolycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Despite the escalating global prevalence, there is currently no definitive predisposition test available for this condition. Among the genetic causes, variations in the mitochondrial DNA (mtDNA) are increasingly recognized as a crucial contributor to the development of PCOS. However, cross-ethnic analysis of these mutations is lacking. To fill in this gap, our objective is to identify new maternal genetic risk factors associated with PCOS by investigating the mitochondrial transfer RNA (mt-tRNA) genes in PCOS patients from Pakistan and to compare these mutations to those in patients from other ethnic groups.MethodsDNA was extracted from saliva samples of patients. Primers were designed for the amplification of all of 22 mt-tRNA genes, and PCR was employed under defined conditions. Subsequently, Sanger sequencing was employed to decipher the sequences of mt-tRNA genes. Following sequencing, mt-tRNA genes underwent mutation analysis. Finally, we utilized MitoTIP (Mitochondrial tRNA Informatics Predictor) to identify variations in mt-tRNA genes.ResultsIn a cohort of 64 Pakistani patients with PCOS, our analysis unveiled eight variants in five mt-tRNA genes including MT-TH, MT-TL2, MT-TS1, MT-TS2, and MT-TT genes. All of these variants have not been previously reported in PCOS except one we have recently identified in a Pakistani patient with PCOS. Interestingly, most of these mt-tRNA genes carry variants found in patients with PCOS across distinct ethnic groups. Furthermore, these mutations occurred in highly conserved nucleotides of tRNA, essential for ensuring the stability and biochemical functionality of mt-tRNA. Finally, the pathogenic potential of these variations was assessed by in silico analysis. The pathogenicity prediction of these variants suggests their potential impact on mitochondrial dysfunction that was responsible for the clinical phenotypes of PCOS.ConclusionOur study identified novel variations in mt-tRNA genes in Pakistani women with PCOS. To our knowledge, this is the first report comparing mutations of mt-tRNA genes in PCOS patients across different ethnic groups. Our data revealed common mt-tRNA genes carrying PCOS-associated mutations that may be specific to certain ethnic populations. Together, our work provides new insights into the role of mt-tRNA genes in mitochondrial dysfunction underlying the pathophysiology of PCOS, highlighting mt-tRNA mutations as potential factors for future predisposition tests and more effective therapies for this globally prevalent condition.

Dataset Information

Analysis of Mitochondrial Transfer RNA Mutations in Breast Cancer.

Publications

Analysis of Mitochondrial Transfer RNA Mutations in Breast Cancer.

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