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Detection of candidate nectin gene mutations in infertile men with severe teratospermia

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

Approximately 40% of infertile men have an abnormal semen analysis, resulting from either abnormalities of sperm production (defective spermatogenesis) or sperm shape (defective spermiogenesis). This latter process is dependent upon the function of Sertoli cells, which maintain specialized junctional complexes with germ cells. Nectins, members of the immunoglobulin superfamily, participate in formation of these dynamic complexes. Male mice in which the nectin-2 or nectin-3 gene is knocked out are sterile. Their spermatozoa exhibit severe teratospermia, altered motility, and an impaired ability to fertilize eggs. We asked whether mutations in the protein coding regions of the nectin-2 (aka PVRL2) and nectin-3 (aka PVRL3) genes could be detected in men from infertile couples whose semen analysis revealed unimpaired sperm production, judged by normal sperm concentration, but severe abnormalities in sperm shape.

Methods

Ejaculates were snap frozen in liquid nitrogen and later submitted for Sanger analysis of these two genes, to detect mutations in their protein coding regions.

Results

Eighty-nine of 455 ejaculates (19.5%) met the inclusion criteria for study. Two of the 56 samples that were successfully analyzed for nectin-2 (3.6%) and one of 73 (1.3%) analyzed for nectin-3 possessed possibly damaging mutations.

Conclusions

Despite the small-scale nature of the study, at least two low-frequency deleterious variants were identified. These results suggest the need for a larger-scale study of sequence variants in the nectins in severe teratospermia.

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References

  1. Thonneau P, Marchand S, Tallec A, Ferial M-L, Ducot B, Lansac J, et al. Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988-1989). Hum Reprod. 1991;6:811–6.

  2. Vogl AW, Vaid KS. Guttman JA. The Sertoli cell cytoskeleton. Adv In Exp Med and Biol 2009; 636: 186 - 211.

  3. Marmar JL. The pathophysiology of varicocoeles in the light of current molecular and genetic information. Hum Reprod Update. 2001;7:461–72.

    Article  CAS  PubMed  Google Scholar 

  4. Carlson E, Andersson AM, Petersen JH, Skakkebaek N. History of febrile illness and variation in semen quality. Hum Reprod. 2003;18:2089–92.

    Article  Google Scholar 

  5. Vine MF, Tse CK, Hu P, Truong KY. Cigarette smoking and semen quality. Fertil Steril. 1996;65:835–42.

    Article  CAS  PubMed  Google Scholar 

  6. Kruger TP, Acosta AA, Simmons KF, Swanson RJ, Matta JF, Veeck LL, et al. New method of evaluating sperm morphology with predictive value for human in vitro fertilization. Urology. 1987;30:246–51.

  7. Bronson RA, Bronson SK, Oula LD. Ability of abnormally-shaped human spermatozoa to adhere to and penetrate zona-free hamster eggs: correlation with sperm morphology and post incubation motility. J Androl. 2007;28:698–705.

    Article  PubMed  Google Scholar 

  8. Samanta D, Ramagopal UA, Rubinstein R, Vigdorovich V, Nathenson SG, Almo SC. Structure of Nectin-2 reveals determinants of hemophilic and heterothallic interactions that control cell-cell adhesion. PNAS. 2010;109:14836–40.

    Article  Google Scholar 

  9. Mueller S, Rosenquist TA, Takai T, Bronson RA, Wimmer E. Loss of nectin-2 at Sertoli-spermatid junctions leads to male fertility and correlates with severe spermatozoon head and midpiece malformation, impaired binding to the zona pellucida and oocyte penetration. Biol Reprod. 2003;69:1330–40.

    Article  CAS  PubMed  Google Scholar 

  10. Inagaki M, Irie K, Ishizaki H, Tanaka-Okamoto M, Miyoshi J, Takai Y. Role of cell adhesion molecule nectin-3 in spermatid development. Genes to Cells. 2006;11:1123–32.

  11. World Health Organization WHO laboratory manual for the examination of human semen and semen-cervical mucus interaction. 4th Ed. Cambridge, United Kingdom, University Press, 1999, 17–22.

  12. Redman JB, Thomas W, Ma W, Drobnes EZ, Sparks A, Wang C, et al. Semen parameters in fertile US men: the study for future families. Andrology. 2013;1(6):806–14.

  13. Rozen S, Skaletsky HJ. Primer3 on the WWW for general users and for biologist programmers. In: Krawetz S, Misener S, editors. Bioinformatics methods and protocols: methods in molecular biology. Totowa: Humana Press; 2000. p. 365–86.

    Google Scholar 

  14. Adzhube I, Jordan, DM, Sunyaev, SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr. Protoc. Hum. Genet. 2013; 0 7: Unit7.20. doi:10.1002/0471142905.hg0720s76.

  15. Wong CH, Cheng CY. The blood-testis barrier: its biology, regulation, and physiological role in spermatogenesis. Cur Top Dev Biol. 2005;71:263–96.

    Article  CAS  Google Scholar 

  16. Massan A, Lissens W, Tournaye H, Stouffs K. Genetic causes of spermatogenic failure. Asian J Andrology. 2014;14:40–8.

    Google Scholar 

  17. Ravel C, Chantot-Bastaraud S, El Houate B, Rouba H, Legendre M, Lorencxo D, et al. Y-chromosome AZFc structural architecture and relationship to male fertility. Fertil Steril. 2009;92:1924–33.

    Article  CAS  PubMed  Google Scholar 

  18. Bashamboo A, Ferraz-Souza B, Lourenco D, Seibire NJ, Montjean D, Bignon-Topalovic J, et al. Human male infertility associated with mutations in NS5A1 encoding steroidogenic factor 1. Am J Human Genet. 2002;87:5005–512.

    Google Scholar 

  19. Imken L, Rouba H, El Houate B, Louanjili N, Barakat A, Chafik A, et al. Mutations in the protamine locus: association with spermatogenic failure. Molec Hum Reprod. 2009;15:733–8.

    Article  CAS  PubMed  Google Scholar 

  20. Montjean D, Zini A, Ravel C, Belloc S, Dalleac A, Copin H, et al. Sperm global DNA methylation level: association with semen parameters and genome integrity. Andrology. 2015;3:235–40.

    Article  CAS  PubMed  Google Scholar 

  21. Eloualid A, Abidi O, Charif M, El Houate B, Beenrahma H, Louanjli N, et al. Association of the MTHFR A1298C variant with unexplained severe male infertility. PLoS One. 2012;7:e3411.

    Google Scholar 

  22. De Boer P, de Vries M, Ramos L. A mutation study of sperm head shape and motility in the mouse: lessons for the clinic. Andrology. 2015;3:174–202.

    Article  PubMed  Google Scholar 

  23. Koscinski I, Elinati E, Fossard C, Rodin C, Muller J, Barratt CLR, et al. DPY19L2 deletion as a major cause of globozoospermia. Am J Hum Gen. 2011;88:344–50.

  24. Zhu F, Gong F, Lin G, Lu G. DPY19L2 gene mutations are a major cause of globospermia: identification of three novel point mutations. Mol Hum Reprod. 2013;19:395–404.

    Article  CAS  PubMed  Google Scholar 

  25. Pierre V, Martinez G, Coutton C, Delaroche J, Yassine S, Novella C, et al. Absence of Dpy1912, a new inner nuclear membrane protein, causes globospermia in mice by preventing the anchoring of the acrosome to the nucleus. Development. 2012;195:673–87.

    Google Scholar 

  26. Coutton C, Escoffier J, Martinez G, Arnoult C, Ray PF. Teratospermia: spotlight on the main genetic actors in the human. Hum Reprod Update. 2015;21:455–85.

    Article  PubMed  Google Scholar 

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Acknowledgements

We acknowledge the skillful work of Susan Bronson and Lucila Oula in the Andrology Lab.

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Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Medicine, Stony Brook University Medical Center, T9-080, Stony Brook, NY, 11794-8091, USA

    Richard Bronson

  2. Department of Anesthesiology, 370 Centers for Molecular Medicine, Stony Brook, NY, 11794-5140, USA

    Anatoly Mikhailik

  3. Genomics Core Facility, Stony Brook University Medical Center, Room 151, Level 5 Basic Sciences Tower, Stony Brook, NY, 11794-8085, USA

    John Schwedes & Dimitri Gnatenko

  4. Department of Pathology, Stony Brook University Medical Center, Stony Brook, NY, 11794, USA

    Eli Hatchwell

Authors
  1. Richard Bronson
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  2. Anatoly Mikhailik
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  3. John Schwedes
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  4. Dimitri Gnatenko
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Corresponding author

Correspondence to Richard Bronson.

Ethics declarations

All procedures performed in studies involving participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Stony Brook University Institutional Review Board [CORIHS No.177570-4], and informed consent was obtained from all individual participants included in the study.

Conflict of interest

The authors declare that they have no conflict of interest.

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Bronson, R., Mikhailik, A., Schwedes, J. et al. Detection of candidate nectin gene mutations in infertile men with severe teratospermia. J Assist Reprod Genet 34, 1295–1302 (2017). https://doi.org/10.1007/s10815-017-0985-4

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  • DOI: https://doi.org/10.1007/s10815-017-0985-4

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