Mitochondrial tRNALeu(UUR) C3275T, tRNAGln T4363C and tRNALys A8343G mutations may be associated with PCOS and metabolic syndrome

Ding, Yu; Xia, Bo‐Hou; Zhang, Caijuan; Zhuo, Guangchao

doi:10.1016/j.gene.2017.11.049

Cited by 63 publications

(56 citation statements)

References 39 publications

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“…In fact, the alteration of the mtDNA copy number, which reflects oxidant-induced cell damage, had been observed in a wide range of human mitochondrial diseases (32). Additionally, a decreased mtDNA copy number has been demonstrated to lead to increased ROS levels; ROS induced by mitochondrial dysfunction can increase mitochondrial Ca 2+ accumulation and may act as potential pathophysiological mechanism in hypertension (33,34).…”

Section: Discussionmentioning

confidence: 99%

The mitochondrial tRNAAla 5587T>C and tRNALeu(CUN) 12280A>G mutations may be associated with hypertension in a Chinese family

et al. 2018

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Hypertension is a very common cardiovascular disorder, however, the molecular mechanism underlying this disease remains poorly understood. Recently, an increasing number of studies have demonstrated that mitochondrial (mt)DNA mutations serve important roles in the pathogenesis of hypertension. The current study reported the clinical and molecular characterization of a Chinese family with maternally inherited hypertension (the penetrance of hypertension was 71.4%). In addition, the entire mitochondrial transfer (mt-t)RNA genomes was amplified using a polymerase chain reaction (PCR) and identified through direct Sanger sequencing. Additionally, the mtDNA copy number in matrilineal relatives in this family was evaluated using quantitative PCR. The sequence analysis of the 22 mt-tRNA genes led to the identification of tRNA Ala 5587T>C (thymine to cytosine) and tRNA Leu(CUN) 12280A>G (adenine to guanine) mutations. Notably, the heteroplasmic 5587T>C mutation was located at the 3' end of tRNA Ala (position 73), which is highly conserved from bacteria to human mitochondria. In addition, the 12280A>G mutation was revealed to occurs at the dihydrouridine loop of tRNA Leu(CUN) (position 15) and may decrease the steady-state level of mt-tRNA. As a result, 5587T>C and 12280A>G mutations may lead to the failure of tRNAs metabolism and subsequently cause mitochondrial protein synthesis defects. Molecular analysis revealed that patients carrying the 5587T>C and 12280A>G mutations had a lower copy number of mtDNA compared with a control with hypertension, but without the mutations, suggesting that these mutations may cause mitochondrial dysfunctions that are responsible for hypertension. Therefore, mt-tRNA Ala 5587T>C and tRNA Leu(CUN) 12280A>G mutations may be involved in the pathogenesis of hypertension in this family.

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Section: Discussionmentioning

confidence: 99%

The mitochondrial tRNAAla 5587T>C and tRNALeu(CUN) 12280A>G mutations may be associated with hypertension in a Chinese family

et al. 2018

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“…Manuscript to be reviewed expression is either significantly different up-or downregulated in PCOS patients compared to controls ( Figure 5). It is interesting to note that mitochondrial tRNA mutations have been previously associated with PCOS [37]. Some of these significantly differentially expressed small RNAs could play mechanistic roles PCOS pathogenesis and should be studied farther.…”

Section: Go and Pathway Analysis Of Mirna Target Genesmentioning

confidence: 99%

Peer Review #2 of "The expression of small RNAs in exosomes of follicular fluid altered in human polycystic ovarian syndrome (v0.1)"

2020

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Polycystic ovary syndrome (PCOS) can cause reproductive disorders that may affect oocyte quality from punctured follicles in human follicular fluid (HFF). The non-coding RNA family includes micro RNA (miRNA), piwi-interacting RNA (piRNA) and transfer RNA (tRNA); these non-coding RNA transcripts play diverse functions and are implicated in a variety of diseases and health conditions, including infertility. In this study, to explore the role of HFF exosomes in PCOS, we extracted and sequenced RNA from HFF exosomes of PCOS patients and compared the analysis results with those of non-PCOS control group. The HFF exosomes were successfully isolated and characterized in a variety of ways. The sequencing results of the HFF exosomal RNA showed that about 6.6% of valid reads in the PCOS group and 8.6% in the non-PCOS group were successfully mapped to the human RNA database. Using hierarchical clustering method, we found there were ten small RNA sequences whose expression was significantly different between the PCOS and non-PCOS groups. We chose 6 of them to predict target genes of interest for further GO analysis, and pathway analysis showed that the target genes are mainly involved in biosynthesis of amino acids, glycine, serine and glycosaminoglycan, as well as threonine metabolism. Therefore, the small RNA sequences contained in HFF EXs may play a key role in the mechanism that drives PCOS pathogenesis, thereby can act as molecular biomarkers for PCOS diagnosis in the future.

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“…Shortly after, a mutation in mitochondrial tRNA Lys was found to cause another rare neurological disorder, myoclonic epilepsy and ragged-red fiber disease (93). Several other mitochondrial tRNA variants are implicated in major human diseases, including heart disease (94), hypertension (95), metabolic disease (96), and deafness (97).…”

Section: Trna Mutants Linked To Diseasementioning

confidence: 99%

Pathways to disease from natural variations in human cytoplasmic tRNAs

Lant

Berg

Heinemann

et al. 2019

Journal of Biological Chemistry

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Edited by Karin Musier-Forsyth Perfectly accurate translation of mRNA into protein is not a prerequisite for life. Resulting from errors in protein synthesis, mistranslation occurs in all cells, including human cells. The human genome encodes >600 tRNA genes, providing both the raw material for genetic variation and a buffer to ensure that resulting translation errors occur at tolerable levels. On the basis of data from the 1000 Genomes Project, we highlight the unanticipated prevalence of mistranslating tRNA variants in the human population and review studies on synthetic and natural tRNA mutations that cause mistranslation or de-regulate protein synthesis. Although mitochondrial tRNA variants are well known to drive human diseases, including developmental disorders, few studies have revealed a role for human cytoplasmic tRNA mutants in disease. In the context of the unexpectedly large number of tRNA variants in the human population, the emerging literature suggests that human diseases may be affected by natural tRNA variants that cause mistranslation or de-regulate tRNA expression and nucleotide modification. This review highlights examples relevant to genetic disorders, cancer, and neurodegeneration in which cytoplasmic tRNA variants directly cause or exacerbate disease and disease-linked phenotypes in cells, animal models, and humans. In the near future, tRNAs may be recognized as useful genetic markers to predict the onset or severity of human disease. This work was supported in part by Natural Sciences and Engineering Research Council of Canada Grants RGPIN 04282-2014 (to P. O.), 530175-2018 (to P. O.), and RGPIN-2015-04394 (to C. J. B.); Canada Foundation for Innovation Grant 229917 (to P. O.); the Ontario Research Fund 229917 (to P. O.); Canada Research Chairs 950-229917 (to P. O.); and the Ontario Centres of Excellence Grant 28922 (to P. O.). This is the first article in the "tRNAs and aminoacyl-tRNA synthetases in human disease" JBC Reviews series. The authors declare that they have no conflicts of interest with the contents of this article. This article contains Tables S1 and S2 and supporting Refs. 1-8. 1 Recipient of a Postgraduate Studies Doctoral Scholarship and supported by the Natural Sciences and Engineering Research Council of Canada. 2 Recipient of a(Canada Graduate Scholarship and supported by the Natural Sciences and Engineering Research Council of Canada and by generous donations from Graham Wright and James Robertson.

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Mitochondrial tRNALeu(UUR) C3275T, tRNAGln T4363C and tRNALys A8343G mutations may be associated with PCOS and metabolic syndrome

Cited by 63 publications

References 39 publications

The mitochondrial tRNAAla 5587T>C and tRNALeu(CUN) 12280A>G mutations may be associated with hypertension in a Chinese family

The mitochondrial tRNAAla 5587T>C and tRNALeu(CUN) 12280A>G mutations may be associated with hypertension in a Chinese family

Peer Review #2 of "The expression of small RNAs in exosomes of follicular fluid altered in human polycystic ovarian syndrome (v0.1)"

Pathways to disease from natural variations in human cytoplasmic tRNAs

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