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Mehdi Heidari, M., Danafar, A., Moezzi, F., Khatami, M., & Reza Talebi, A. (2019). The association between TNP2 gene polymorphisms and Iranian infertile men with varicocele: A case-control study. International Journal of Reproductive BioMedicine (IJRM), 17(8), 557–566. https://doi.org/10.18502/ijrm.v17i8.4821
https://doi.org/10.18502/ijrm.v17i8.4821
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- Cited by 3 articles
authors
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Mohammad Mehdi Heidari
Mohammad Mehdi Heidari
Department of Biology, Faculty of Science, Yazd University, Yazd, Iran
-
Amirhossein Danafar
Amirhossein Danafar
Department of Biology, Ashkezar Islamic Azad University, Ashkezar, Yazd, Iran
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Fahime Moezzi
Fahime Moezzi
Department of Biology, Faculty of Science, Yazd University, Yazd, Iran
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Mehri Khatami
Mehri Khatami
Department of Biology, Faculty of Science, Yazd University, Yazd, Iran
-
Ali Reza Talebi
Ali Reza Talebi
Research and Clinical Center for Infertility and Department of Anatomy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
Published Date
- Sep 3, 2019
The association between TNP2 gene polymorphisms and Iranian infertile men with varicocele: A case-control study
Abstract
Background: Numerous researches have provided great evidence that revealed the relationship between varicocele and sperm DNA damage.
Objective: Because of the crucial role of nuclear transition proteins (TPs) in sperm DNA condensation and integrity, this case-control study was designed to study TNP2 gene nucleotide variations in Iranian patients with varicocele.
Materials and Methods: PCR-SSCP and DNA sequencing were used to search for mutations in exons 1 & 2 of the TNP2 gene in 156 infertile patients with varicocele and 150 fertile men.
Results: The results of sequencing showed three variants at positions c.301C > T (p.R101C), c.391C > T (p.R131 W), and g.IVS1-26G >C (rs8043625) of TNP2 gene. It was found that varicocele risk in men who have the CC genotype of g.IVS1-26G >C SNP is higher than those who don’t have these genotypes (according to Co-dominant model, Dominant model, Recessive model, and Over-dominant model). The haplotype-based analysis showed that (C/C/T) and (C/T/T) haplotypes were a risk factor of in patients with varicocele compared to controls (OR = 3.278, p = 0.000 and OR= 9.304, p = 0.038, respectively).
Conclusion: Because of the significant difference in the genotype and allele frequencies of g.IVS1-26G >C SNP in the intronic region of TNP2 in patients with varicocele compared with controls and also because of the high conservation of this SNP position during evolution, this SNP may be involved in some important processes associated with the expression of this gene like mRNA splicing, but the exact mechanism is not clear.
References
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[2] Skoog SJ, Roberts KP, Goldstein M, Pryor JL. The adolescent varicocele: what’s new with an old problem in young patients?. Pediatrics 1997; 100: 112–121.
[3] Oliveira A, Neto A, Almeida C, Silva-Ramos M, Versos R, Barros A, et al. Comparative study of gene expression in patients with varicocele by microarray technology. Andrologia 2012; 44 (Suppl.): 260–265.
[4] Johnson CW, Fisch H, Hensle TW. The adolescent varicocele. AUA Update Series 2004; 23: 265–271.
[5] Zhao M, Shirley CR, Hayashi S, Marcon L, Mohapatra B, Suganuma R, et al. Transition nuclear proteins are required for normal chromatin condensation and functional sperm development. Genesis 2004; 38: 200–213.
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[14] Saleh RA, Agarwal A, Sharma RK, Said TM, Sikka SC, Thomas AJ. Jr Evaluation of nuclear DNA damage in spermatozoa from infertile men with varicocele. Fertil Steril 2003; 80: 1431–1436.
[15] Talebi AR, Moein MR, Tabibnejad N, Ghasemzadeh J. Effect of varicocele on chromatin condensation and DNA integrity of ejaculated spermatozoa using cytochemical tests. Andrologia 2008; 40: 245–251.
[16] Meistrich ML, Mohapatra B, Shirley CR, Zhao M. Roles of transition nuclear proteins in spermiogenesis. Chromosoma 2003; 111: 483–488.
[17] Bukowska D, Kempisty B, Piotrowska H, Sosinska P,Wozna M, Ciesiolka S, et al. The structure and role of mammalian sperm RNA: a review. Veterinarni Medicina 2013; 58: 57–64.
[18] Tanaka H, Baba T. Gene expression in spermiogenesis. Cell Mol Life Sci 2005; 62: 344–354.
[19] Venkatesh S, Kumar R, Deka D, Deecaraman M, Dada R. Analysis of sperm nuclear protein gene polymorphisms and DNA integrity in infertile men. Syst Biol Reprod Med 2011; 57: 124–132.
[20] Nelson JE, Krawetz SA. Characterization of a human locus in transition. J Biol Chem 1994; 269: 31067–31073.
[21] Shaw MA, Clayton D, Atkinson SE, Williams H, Miller N, Sibthorpe D, et al. Linkage of rheumatoid arthritis to the candidate gene NRAMP1 on 2q35. J Med Genet 1996; 33: 672–677.
[22] Heidari MM, Khatami M, Talebi AR, Moezzi F. Mutation analysis of TNP1 gene in infertile men with varicocele. Iran J Reprod Med 2014; 12: 257–262.
[23] Organization WHO. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. UK, Cambridge university press; 1999.
[24] Shu JH, Feng GX, Li J, Li JX, Gan XY, Zhang B, et al. [Predictive value of sperm morphology according to WHO Laboratory Manual for the Examination and Processing of Human Semen (5th Ed) on the outcomes of IVF-ET]. Zhonghua Nan Ke Xue 2013; 19: 414–417.
[25] World Health Organization.[Laboratory manual of the WHO for the examination of human semen and sperm-cervical mucus interaction]. Ann Ist Super Sanita 2001; 37: 1–123. (in Persian)
[26] Hayashi K. PCR-SSCP: a simple and sensitive method for detection of mutations in the genomic DNA. PCR Methods Appl 1991; 1: 34–38.
[27] Haas J, Roth S, Arnold K, Kiefer F, Schmidt T, Bordoli L, et al. The protein model portal–a comprehensive resource for protein structure and model information. Database 2013; 2013: bat031.
[28] Ravel C, Chantot-Bastaraud S, El Houate B, Berthaut I, Verstraete L, De Larouziere V, et al. Mutations in the protamine 1 gene associated with male infertility. Mol Hum Reprod 2007; 13: 461–464.
[29] Adham IM, Nayernia K, Burkhardt-Gottges E, Topaloglu O, Dixkens C, Holstein AF, et al. Teratozoospermia in mice lacking the transition protein 2 (Tnp2). Mol Hum Reprod 2001; 7: 513–520.
[30] Lewis JD, Saperas N, Song Y, Zamora MJ, Chiva M, Ausio J. Histone H1 and the origin of protamines. Proc Natl Acad Sci U S A 2004; 101: 4148–4152.
[31] Nayeri M, Talebi AR, Heidari MM, Seifati SM, Tabibnejad N. Polymorphisms of sperm protamine genes and CMA3 staining in infertile men with varicocele. Rev Int Androl 2018; 7: doi: 10.1016/j.androl.2018.07.005.
[32] Nistal M, Gonzalez-Peramato P, Serrano A, Regadera J. [Physiopathology of the infertile testicle. Etiopathogenesis of varicocele]. Arch Esp Urol 2004; 57: 883–904.
[33] Imken L, Rouba H, El Houate B, Louanjli N, Barakat A, Chafik A, et al. Mutations in the protamine locus: association with spermatogenic failure?. Mol Hum Reprod 2009; 15: 733–738.
[34] Siasi E, Aleyasin A, Mowla J, Sahebkashaf H. Association study of six SNPs in PRM1, PRM2 and TNP2 genes in iranian infertile men with idiopathic azoospermia. Iran J Reprod Med 2012; 10: 329–336.
[35] Miyagawa Y, Nishimura H, Tsujimura A, Matsuoka Y, Matsumiya K, Okuyama A, et al. Single-nucleotide polymorphisms and mutation analyses of the TNP1 and TNP2 genes of fertile and infertile human male populations. J Androl 2005; 26: 779–786.
[36] Baskaran R, Rao MR. Interaction of spermatid-specific protein TP2 with nucleic acids, in vitro. A comparative study with TP1. J Biol Chem 1990; 265: 21039–21047.
[2] Skoog SJ, Roberts KP, Goldstein M, Pryor JL. The adolescent varicocele: what’s new with an old problem in young patients?. Pediatrics 1997; 100: 112–121.
[3] Oliveira A, Neto A, Almeida C, Silva-Ramos M, Versos R, Barros A, et al. Comparative study of gene expression in patients with varicocele by microarray technology. Andrologia 2012; 44 (Suppl.): 260–265.
[4] Johnson CW, Fisch H, Hensle TW. The adolescent varicocele. AUA Update Series 2004; 23: 265–271.
[5] Zhao M, Shirley CR, Hayashi S, Marcon L, Mohapatra B, Suganuma R, et al. Transition nuclear proteins are required for normal chromatin condensation and functional sperm development. Genesis 2004; 38: 200–213.
[6] Hassun Filho PA, Cedenho AP, Lima SB, Ortiz V, Srougi M. Single nucleotide polymorphisms of the heat shock protein 90 gene in varicocele-associated infertility. Int Braz J Urol 2005; 31: 236–242.
[7] Jarow JP. Effects of varicocele on male fertility.HumReprod Update 2001; 7: 59–64.
[8] Abdel-Meguid TA, Al-Sayyad A, Tayib A, Farsi HM. Does varicocele repair improve male infertility? An evidence-based perspective from a randomized, controlled trial. Eur Urol 2011; 59: 455–461.
[9] Naderi G, Mohseni Rad H, Tabassomi F, Latif A. Seminal insulin-like growth factor-I may be involved in the pathophysiology of infertility among patients with clinical varicocele. Hum Fertil 2015; 18: 92–95.
[10] Wang YJ, Zhang RQ, Lin YJ, Zhang RG, Zhang WL. Relationship between varicocele and sperm DNA damage and the effect of varicocele repair: a meta-analysis. Reprod Biomed Online 2012; 25: 307–314.
[11] Garc´ıa-Peiro´ A, Oliver-Bonet M, Navarro J, Abad C, Amengual MJ, Lo´ pez-Ferna´ ndez C, et al. Differential clustering of sperm subpopulations in infertile males with clinical varicocele and carriers of rearranged genomes. J Androl 2012; 33: 361–367.
[12] Bertolla RP, Cedenho AP, Hassun Filho PA, Lima SB, Ortiz V, Srougi M. Sperm nuclear DNA fragmentation in adolescents with varicocele. Fertil Steril 2006; 85: 625–628.
[13] Blumer CG, Fariello RM, Restelli AE, Spaine DM, Bertolla RP, Cedenho AP. Sperm nuclear DNA fragmentation and mitochondrial activity in men with varicocele. Fertil Steril 2008; 90: 1716–1722.
[14] Saleh RA, Agarwal A, Sharma RK, Said TM, Sikka SC, Thomas AJ. Jr Evaluation of nuclear DNA damage in spermatozoa from infertile men with varicocele. Fertil Steril 2003; 80: 1431–1436.
[15] Talebi AR, Moein MR, Tabibnejad N, Ghasemzadeh J. Effect of varicocele on chromatin condensation and DNA integrity of ejaculated spermatozoa using cytochemical tests. Andrologia 2008; 40: 245–251.
[16] Meistrich ML, Mohapatra B, Shirley CR, Zhao M. Roles of transition nuclear proteins in spermiogenesis. Chromosoma 2003; 111: 483–488.
[17] Bukowska D, Kempisty B, Piotrowska H, Sosinska P,Wozna M, Ciesiolka S, et al. The structure and role of mammalian sperm RNA: a review. Veterinarni Medicina 2013; 58: 57–64.
[18] Tanaka H, Baba T. Gene expression in spermiogenesis. Cell Mol Life Sci 2005; 62: 344–354.
[19] Venkatesh S, Kumar R, Deka D, Deecaraman M, Dada R. Analysis of sperm nuclear protein gene polymorphisms and DNA integrity in infertile men. Syst Biol Reprod Med 2011; 57: 124–132.
[20] Nelson JE, Krawetz SA. Characterization of a human locus in transition. J Biol Chem 1994; 269: 31067–31073.
[21] Shaw MA, Clayton D, Atkinson SE, Williams H, Miller N, Sibthorpe D, et al. Linkage of rheumatoid arthritis to the candidate gene NRAMP1 on 2q35. J Med Genet 1996; 33: 672–677.
[22] Heidari MM, Khatami M, Talebi AR, Moezzi F. Mutation analysis of TNP1 gene in infertile men with varicocele. Iran J Reprod Med 2014; 12: 257–262.
[23] Organization WHO. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. UK, Cambridge university press; 1999.
[24] Shu JH, Feng GX, Li J, Li JX, Gan XY, Zhang B, et al. [Predictive value of sperm morphology according to WHO Laboratory Manual for the Examination and Processing of Human Semen (5th Ed) on the outcomes of IVF-ET]. Zhonghua Nan Ke Xue 2013; 19: 414–417.
[25] World Health Organization.[Laboratory manual of the WHO for the examination of human semen and sperm-cervical mucus interaction]. Ann Ist Super Sanita 2001; 37: 1–123. (in Persian)
[26] Hayashi K. PCR-SSCP: a simple and sensitive method for detection of mutations in the genomic DNA. PCR Methods Appl 1991; 1: 34–38.
[27] Haas J, Roth S, Arnold K, Kiefer F, Schmidt T, Bordoli L, et al. The protein model portal–a comprehensive resource for protein structure and model information. Database 2013; 2013: bat031.
[28] Ravel C, Chantot-Bastaraud S, El Houate B, Berthaut I, Verstraete L, De Larouziere V, et al. Mutations in the protamine 1 gene associated with male infertility. Mol Hum Reprod 2007; 13: 461–464.
[29] Adham IM, Nayernia K, Burkhardt-Gottges E, Topaloglu O, Dixkens C, Holstein AF, et al. Teratozoospermia in mice lacking the transition protein 2 (Tnp2). Mol Hum Reprod 2001; 7: 513–520.
[30] Lewis JD, Saperas N, Song Y, Zamora MJ, Chiva M, Ausio J. Histone H1 and the origin of protamines. Proc Natl Acad Sci U S A 2004; 101: 4148–4152.
[31] Nayeri M, Talebi AR, Heidari MM, Seifati SM, Tabibnejad N. Polymorphisms of sperm protamine genes and CMA3 staining in infertile men with varicocele. Rev Int Androl 2018; 7: doi: 10.1016/j.androl.2018.07.005.
[32] Nistal M, Gonzalez-Peramato P, Serrano A, Regadera J. [Physiopathology of the infertile testicle. Etiopathogenesis of varicocele]. Arch Esp Urol 2004; 57: 883–904.
[33] Imken L, Rouba H, El Houate B, Louanjli N, Barakat A, Chafik A, et al. Mutations in the protamine locus: association with spermatogenic failure?. Mol Hum Reprod 2009; 15: 733–738.
[34] Siasi E, Aleyasin A, Mowla J, Sahebkashaf H. Association study of six SNPs in PRM1, PRM2 and TNP2 genes in iranian infertile men with idiopathic azoospermia. Iran J Reprod Med 2012; 10: 329–336.
[35] Miyagawa Y, Nishimura H, Tsujimura A, Matsuoka Y, Matsumiya K, Okuyama A, et al. Single-nucleotide polymorphisms and mutation analyses of the TNP1 and TNP2 genes of fertile and infertile human male populations. J Androl 2005; 26: 779–786.
[36] Baskaran R, Rao MR. Interaction of spermatid-specific protein TP2 with nucleic acids, in vitro. A comparative study with TP1. J Biol Chem 1990; 265: 21039–21047.