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Mojodi, E., Mehrjardi, A. M., Naeimzadeh, Y., Ghasemi, N., Falahati, A., & Moshtaghioun, S. M. (2023). The sequence variation of mitochondrial tRNA tyrosine and cysteine among Iranian women with idiopathic recurrent miscarriage: A case-control study. International Journal of Reproductive BioMedicine (IJRM), 21(7), 567–576. https://doi.org/10.18502/ijrm.v21i7.13894
https://doi.org/10.18502/ijrm.v21i7.13894
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authors
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Elham Mojodi
Elham Mojodi
Department of Biology, Faculty of Science, Yazd University, Yazd, Iran.
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Alimohammad Mosadegh Mehrjardi
Alimohammad Mosadegh Mehrjardi
Department of Traditional Pharmacy, Faculty of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Yasaman Naeimzadeh
Yasaman Naeimzadeh
Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
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Nasrin Ghasemi
Nasrin Ghasemi
Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Ali Falahati
Ali Falahati
Department of Biology, Faculty of Science, Yazd University, Yazd, Iran.
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Seyed Mohammad Moshtaghioun
Seyed Mohammad Moshtaghioun
Department of Biology, Faculty of Science, Yazd University, Yazd, Iran.
Published Date
- Aug 19, 2023
The sequence variation of mitochondrial tRNA tyrosine and cysteine among Iranian women with idiopathic recurrent miscarriage: A case-control study
Abstract
Background: Recurrent miscarriage is one of the most prevalent reproductive diseases. This phenomenon has several reasons, including maternal, hormonal, immunological, and parental genetic factors. Idiopathic recurrent miscarriage (IRM), with no distinctive etiology, involves about half of the recurrent miscarriage cases. Some mutations in mitochondrial DNA can lead to miscarriage. Mitochondrial tRNA (mt-tRNA) mutations cause nearly half of the mitochondrial disorders.
Objective: To identify mt- tRNACys & Tyr gene mutations in Iranian women with IRM.
Materials and Methods: In this case-control study, 100 Iranian women with IRM and 100 women as control without any history of miscarriage were investigated by polymerase chain reaction-single strand conformation polymorphism technique followed by gene sequencing. Bioinformatics analysis were done using human mitochondrial genome database, molecular evolutionary genetics analysis, mammalian mitochondrial-tRNA, etc.
Results: Results showed 4 mt-tRNA mutations including 1 cysteine mt-tRNA mutation (5824C>T) and 3 tyrosine mt-tRNA mutations (5868T>A, 5849C>T, and 5836T>C) in our cases.
Conclusion: Amongst the 4 mutations found, one was novel that is still not reported. Our bioinformatics analysis revealed that these mutations can be pathogenic. They occurred in tRNA-conserved regions and their secondary structure was changed, which can result in mitochondrial dysfunction. Mutations of these genes may help in the assessment of IRM. Further study of all 22 mt-tRNAs possible mutations is recommended to describe their etiologic role in IRM.
Key words: Recurrent early pregnancy loss, mtDNA, SNPs, Heteroplasmy.
References
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[11] Cho S-I, Lee S, Mok YG, Lim K, Lee J, Lee JM, et al. Targeted A-to-G base editing in human mitochondrial DNA with programmable deaminases. Cell 2022; 185: 1764-1776.
[12] De Gaetano A, Solodka K, Zanini G, Selleri V, Mattioli AV, Nasi M, et al. Molecular mechanisms of mtdnamediated inflammation. Cells 2021; 10: 2898.
[13] Cai H, Chen L, Zhang M, Xiang W, Su P. Low expression of MFN2 is associated with early unexplained miscarriage by regulating autophagy of trophoblast cells. Placenta 2018; 70: 34-40.
[14] Khodadadian A, Varghaiyan Y, Babakhanzadeh E, Alipourfard I, Haghi-Daredeh S, Ghobadi A, et al. Fertility preservation in women with ovarian cancer: Finding new pathways: A case-control study. Int J Reprod BioMed 2021; 19: 157-166.
[15] de Almeida RA, Fraczek MG, Parker S, Delneri D, O’Keefe RT. Non-coding RNAs and disease: The classical ncRNAs make a comeback. Biochem Soc Trans 2016; 44: 1073-1078.
[16] Simoncini C, Montano V, Alì G, Costa R, Siciliano G, Mancuso M. Proximal myopathy due to m. 5835G> A mutation in mitochondrial MT-TY gene. Case Rep Neurol Med 2018; 2018: 8406712.
[17] Su M-T, Lin S-H, Chen Y-C. Genetic association studies of angiogenesis-and vasoconstriction-related genes in women with recurrent pregnancy loss: A systematic review and meta-analysis. Hum Reprod Update 2011; 17: 803-812.
[18] Yarham JW, Elson JL, Blakely EL, McFarland R, Taylor RW. Mitochondrial tRNA mutations and disease. Wiley Interdiscip Rev RNA 2010; 1: 304-324.
[19] Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, et al. Deficient methylation and formylation of mt-tRNA Met wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun 2016; 7: 12039.
[20] Govender P, Fashoto SG, Maharaj L, Adeleke MA, Mbunge E, Olamijuwon J, et al. The application of machine learning to predict genetic relatedness using human mtDNA hypervariable region I sequences. PloS One 2022; 17: e0263790.
[21] Soler-Alfonso C, Pillai N, Cooney E, Mysore KR, Boyer S, Scaglia F. L-Cysteine supplementation prevents liver transplantation in a patient with TRMU deficiency. Mol Genet Metab Rep 2019; 19: 100453.
[22] Wang D, Ning C, Xiang H, Zheng X, Kong M, Yin T, et al. Polymorphism of mitochondrial tRNA genes associated with the number of pigs born alive. J Anim Sci Biotechnol 2018; 9: 86.
[23] Babakhanzadeh E, Danaei H, Abedinzadeh M, Ashrafzadeh HR, Ghasemi N. Association of miR- 146a and miR196a2 genotype with susceptibility to idiopathic recurrent pregnancy loss in Iranian women: A case-control study. Int J Reprod BioMed 2021; 19: 725-732.
[24] Ding Y, Xia B-H, Zhang C-J, Zhuo G-C. Mutations in mitochondrial tRNA genes may be related to insulin resistance in women with polycystic ovary syndrome. Am J Transl Res 2017; 9: 2984-2996.
[25] Ng YS, Lim AZ, Panagiotou G, Turnbull DM, Walker M. Endocrine manifestations and new developments in mitochondrial disease. Endocr Rev 2022; 43: 583-609.
[26] Sissler M, Gonzalez-Serrano LE, Westhof E. Recent advances in mitochondrial aminoacyl-tRNA synthetases and disease. Trends Mol Med 2017; 23: 693-708.
[27] Webb BD, Diaz GA, Prasun P. Mitochondrial translation defects and human disease. J Transl Genet Genom 2020; 4: 71-80.
[28] Pang W, Zhang Y, Zhao N, Darwiche SS, Fu X, Xiang W. Low expression of Mfn2 is associated with mitochondrial damage and apoptosis in the placental villi of early unexplained miscarriage. Placenta 2013; 34: 613-618.
[29] Wei D, Wu Q, Shi H. Apoptosis and p53 expression in the placental villi of females with unexplained recurrent spontaneous abortion. Exp Ther Med 2014; 7: 191-194.
[2] Marquard K, Westphal LM, Milki AA, Lathi RB. Etiology of recurrent pregnancy loss in women over the age of 35 years. Fertil Steril 2010; 94: 1473-1477.
[3] Busnelli A, Somigliana E, Cirillo F, Levi-Setti PE. Is diminished ovarian reserve a risk factor for miscarriage? Results of a systematic review and meta-analysis. Hum Reprod Update 2021; 27: 973-988.
[4] Devall AJ, Papadopoulou A, Podesek M, Haas DM, Price MJ, Coomarasamy A, et al. Progestogens for preventing miscarriage: A network meta−analysis. Cochrane Database Syst Rev 2021; 4: CD013792.
[5] Von Woon E, Greer O, Shah N, Nikolaou D, Johnson M, Male V. Number and function of uterine natural killer cells in recurrent miscarriage and implantation failure: A systematic review and meta-analysis. Hum Reprod Update 2022; 28: 548-582.
[6] Laisk T, Soares ALG, Ferreira T, Painter JN, Censin JC, Laber S, et al. The genetic architecture of sporadic and multiple consecutive miscarriage. Nat Commun 2020; 11: 5980.
[7] Tang Y, Zhang X, Zhang Y, Feng H, Gao J, Liu H, et al. Senescent changes and endoplasmic reticulum stress may be involved in the pathogenesis of missed miscarriage. Front Cell Dev Biol 2021; 9: 656549.
[8] Duran−Retamal M, Morris G, Achilli C, Gaunt M, Theodorou E, Saab W, et al. Live birth and miscarriage rate following intracytoplasmic morphologically selected sperm injection vs intracytoplasmic sperm injection: An updated systematic review and meta−analysis. Acta Obstet Gynecol Scand 2020; 99: 24-33.
[9] Silva S, Camino LP, Aguilera A. Human mitochondrial degradosome prevents harmful mitochondrial R loops and mitochondrial genome instability. Proc Nati Acad Sci USA 2018; 115: 11024-11029.
[10] O’Keefe H, Queen R, Lord P, Elson JL. What can a comparative genomics approach tell us about the pathogenicity of mtDNA mutations in human populations? Evol Appl 2019; 12: 1912-1930.
[11] Cho S-I, Lee S, Mok YG, Lim K, Lee J, Lee JM, et al. Targeted A-to-G base editing in human mitochondrial DNA with programmable deaminases. Cell 2022; 185: 1764-1776.
[12] De Gaetano A, Solodka K, Zanini G, Selleri V, Mattioli AV, Nasi M, et al. Molecular mechanisms of mtdnamediated inflammation. Cells 2021; 10: 2898.
[13] Cai H, Chen L, Zhang M, Xiang W, Su P. Low expression of MFN2 is associated with early unexplained miscarriage by regulating autophagy of trophoblast cells. Placenta 2018; 70: 34-40.
[14] Khodadadian A, Varghaiyan Y, Babakhanzadeh E, Alipourfard I, Haghi-Daredeh S, Ghobadi A, et al. Fertility preservation in women with ovarian cancer: Finding new pathways: A case-control study. Int J Reprod BioMed 2021; 19: 157-166.
[15] de Almeida RA, Fraczek MG, Parker S, Delneri D, O’Keefe RT. Non-coding RNAs and disease: The classical ncRNAs make a comeback. Biochem Soc Trans 2016; 44: 1073-1078.
[16] Simoncini C, Montano V, Alì G, Costa R, Siciliano G, Mancuso M. Proximal myopathy due to m. 5835G> A mutation in mitochondrial MT-TY gene. Case Rep Neurol Med 2018; 2018: 8406712.
[17] Su M-T, Lin S-H, Chen Y-C. Genetic association studies of angiogenesis-and vasoconstriction-related genes in women with recurrent pregnancy loss: A systematic review and meta-analysis. Hum Reprod Update 2011; 17: 803-812.
[18] Yarham JW, Elson JL, Blakely EL, McFarland R, Taylor RW. Mitochondrial tRNA mutations and disease. Wiley Interdiscip Rev RNA 2010; 1: 304-324.
[19] Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, et al. Deficient methylation and formylation of mt-tRNA Met wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun 2016; 7: 12039.
[20] Govender P, Fashoto SG, Maharaj L, Adeleke MA, Mbunge E, Olamijuwon J, et al. The application of machine learning to predict genetic relatedness using human mtDNA hypervariable region I sequences. PloS One 2022; 17: e0263790.
[21] Soler-Alfonso C, Pillai N, Cooney E, Mysore KR, Boyer S, Scaglia F. L-Cysteine supplementation prevents liver transplantation in a patient with TRMU deficiency. Mol Genet Metab Rep 2019; 19: 100453.
[22] Wang D, Ning C, Xiang H, Zheng X, Kong M, Yin T, et al. Polymorphism of mitochondrial tRNA genes associated with the number of pigs born alive. J Anim Sci Biotechnol 2018; 9: 86.
[23] Babakhanzadeh E, Danaei H, Abedinzadeh M, Ashrafzadeh HR, Ghasemi N. Association of miR- 146a and miR196a2 genotype with susceptibility to idiopathic recurrent pregnancy loss in Iranian women: A case-control study. Int J Reprod BioMed 2021; 19: 725-732.
[24] Ding Y, Xia B-H, Zhang C-J, Zhuo G-C. Mutations in mitochondrial tRNA genes may be related to insulin resistance in women with polycystic ovary syndrome. Am J Transl Res 2017; 9: 2984-2996.
[25] Ng YS, Lim AZ, Panagiotou G, Turnbull DM, Walker M. Endocrine manifestations and new developments in mitochondrial disease. Endocr Rev 2022; 43: 583-609.
[26] Sissler M, Gonzalez-Serrano LE, Westhof E. Recent advances in mitochondrial aminoacyl-tRNA synthetases and disease. Trends Mol Med 2017; 23: 693-708.
[27] Webb BD, Diaz GA, Prasun P. Mitochondrial translation defects and human disease. J Transl Genet Genom 2020; 4: 71-80.
[28] Pang W, Zhang Y, Zhao N, Darwiche SS, Fu X, Xiang W. Low expression of Mfn2 is associated with mitochondrial damage and apoptosis in the placental villi of early unexplained miscarriage. Placenta 2013; 34: 613-618.
[29] Wei D, Wu Q, Shi H. Apoptosis and p53 expression in the placental villi of females with unexplained recurrent spontaneous abortion. Exp Ther Med 2014; 7: 191-194.