Skip to main content

Advertisement

SpringerLink
Log in

Duplications in 19p13.3 are associated with male infertility

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

Abstract

Purpose

To identify genomic imbalances and candidate loci in idiopathic male infertility.

Methods

Affymetrix CytoScan 750K Array was used to analyze genomic imbalances and candidate loci in 34 idiopathic infertile cases of different phenotypes (hypo-spermatogenesis, n = 8; maturation arrest, n = 7; and Sertoli cell-only syndrome, n = 13, severe oligozoospermia, n = 6, and 10 normozoospermic fertile men). Ten ethnically matched controls were screened for comparison.

Results

The cytogenetic array analysis detected a genomic gain at the 19p13.3 region in 9 (26.47%) cases, with the highest frequency in patients with Sertoli cell-only syndrome (SCOS) (38%). Its complete absence in the control group suggests its likely pathogenic nature. In addition to Y-classical, micro, and partial deletions, the duplication in 19p13.3 could serve as a unique biomarker for evaluation of infertility risk. The common region across the individuals harboring the duplication identified STK11, ATP5D, MIDN, CIRBP, and EFNA2 genes which make them strong candidates for further investigations. The largest duplicated region identified in this study displayed a major network of 7 genes, viz., CIRBP, FSTL3, GPX4, GAMT, KISS1R, STK11, and PCSK4, associated with reproductive system development and function. The role of chance was ruled out by screening of ethnically matched controls.

Conclusion

The result clearly indicates the significance of 19p13.3 duplication in infertile men with severe testicular phenotypes. The present study underlines the utility and significance of whole genomic analysis in the cases of male infertility which goes undiagnosed due to limitations in the conventional cytogenetic techniques and for identifying genes that are essential for spermatogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Holden CA, McLachlan RI, Pitts M, Cumming R, Wittert G, Agius PA, et al. Men in Australia Telephone Survey (MATeS): a national survey of the reproductive health and concerns of middle-aged and older Australian men. Lancet. 2005;366:218–24.

    Article  PubMed  Google Scholar 

  2. Matzuk MM, Lamb DJ. The biology of infertility: research advances and clinical challenges. Nat Med. 2008;14:1197–213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Baker G, Barak S (2012) Clinical management of male infertility. wwwENDOTEXTorg Chapter 7: MDTEXT. COM. Inc, South Dartmouth, MA, USA.

  4. Pastuszak AW, Lamb DJ. The genetics of male fertility—from basic science to clinical evaluation. J Androl. 2012;33:1075–84.

    Article  CAS  PubMed  Google Scholar 

  5. McLachlan RI, O’bryan MK. State of the art for genetic testing of infertile men. J Clin Endocrinol Metab. 2010;95:1013–24.

    Article  CAS  PubMed  Google Scholar 

  6. Diemer T, Desjardins C. Developmental and genetic disorders in spermatogenesis. Hum Reprod Update. 1999;5:120–40.

    Article  CAS  PubMed  Google Scholar 

  7. Yang L, Xu L, Zhou Y, Liu M, Wang L, Kijas JW, et al. Diversity of copy number variation in a worldwide population of sheep. Genomics. 2018;110:143–8.

    Article  CAS  PubMed  Google Scholar 

  8. Feuk L, Carson AR, Scherer SW. Structural variation in the human genome. Nat Rev Genet. 2006;7:85–97.

    Article  CAS  PubMed  Google Scholar 

  9. Jaillard S, Drunat S, Bendavid C, Aboura A, Etcheverry A, Journel H, et al. Identification of gene copy number variations in patients with mental retardation using array-CGH: novel syndromes in a large French series. Eur J Med Genet. 2010;53:66–75.

    Article  PubMed  Google Scholar 

  10. Kumaran M, Cass CE, Graham K, Mackey JR, Hubaux R, Lam W, et al. Germline copy number variations are associated with breast cancer risk and prognosis. Sci Rep. 2017;7:14621.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Marshall CR, Howrigan DP, Merico D, Thiruvahindrapuram B, Wu W, Greer DS, et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet. 2017;49:27–35.

    Article  CAS  PubMed  Google Scholar 

  12. Xie Y, Yuan H, Wang M, Zhong L, Zhou J, Song B, Yin Q, Sun X. Copy number variations independently induce autism spectrum disorder. Biosci Rep 2017;37:BSR20160570.

  13. Eggers S, DeBoer KD, van den Bergen J, Gordon L, White SJ, Jamsai D, et al. Copy number variation associated with meiotic arrest in idiopathic male infertility. Fertil Steril. 2015;103:214–9.

    Article  PubMed  Google Scholar 

  14. Stouffs K, Vandermaelen D, Massart A, Menten B, Vergult S, Tournaye H, et al. Array comparative genomic hybridization in male infertility. Hum Reprod. 2012;27:921–9.

    Article  CAS  PubMed  Google Scholar 

  15. White S, Ohnesorg T, Notini A, Roeszler K, Hewitt J, Daggag H, et al. Copy number variation in patients with disorders of sex development due to 46, XY gonadal dysgenesis. PLoS One. 2011;6:e17793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jaiswal D, Singh V, Dwivedi US, Trivedi S, Singh K. Chromosome microarray analysis: a case report of infertile brothers with CATSPER gene deletion. Gene. 2014;542:263–5.

    Article  CAS  PubMed  Google Scholar 

  17. Vermeesch JR, Brady PD, Sanlaville D, Kok K, Hastings RJ. Genome-wide arrays: quality criteria and platforms to be used in routine diagnostics. Hum Mutat. 2012;33:906–15.

    Article  CAS  PubMed  Google Scholar 

  18. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Saeki H, Kitao H, Yoshinaga K, Nakanoko T, Kubo N, Kakeji Y, et al. Copy-neutral loss of heterozygosity at the p53 locus in carcinogenesis of esophageal squamous cell carcinomas associated with p53 mutations. Clin Cancer Res. 2011;17:1731–40.

    Article  CAS  PubMed  Google Scholar 

  20. Saare M, Soritsa D, Vaidla K, Palta P, Remm M, Laan M, et al. No evidence of somatic DNA copy number alterations in eutopic and ectopic endometrial tissue in endometriosis. Hum Reprod. 2012;27:1857–64.

    Article  CAS  PubMed  Google Scholar 

  21. Grimwood J, Gordon LA, Olsen A, Terry A, Schmutz J, Lamerdin J, et al. The DNA sequence and biology of human chromosome 19. Nature. 2004;428:529–35.

    Article  CAS  PubMed  Google Scholar 

  22. Ishikawa A, Enomoto K, Tominaga M, Saito T, Nagai J, Furuya N, et al. Pure duplication of 19p13. 3. Am J Med Genet A. 2013;161:2300–4.

    Article  CAS  Google Scholar 

  23. Nevado J, Rosenfeld JA, Mena R, Palomares-Bralo M, Vallespín E, Mori MÁ, et al. PIAS4 is associated with macro/microcephaly in the novel interstitial 19p13. 3 microdeletion/microduplication syndrome. Eur J Hum Genet. 2015;23:1615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Archer HL, Gupta S, Enoch S, Thompson P, Rowbottom A, Chua I, et al. Distinct phenotype associated with a cryptic subtelomeric deletion of 19p13. 3-pter. Am J Med Genet A. 2005;136:38–44.

    Article  CAS  PubMed  Google Scholar 

  25. Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HWG, Behre HM, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010;16:231–45.

    Article  PubMed  Google Scholar 

  26. Singh V, Bansal SK, Singh R, Singh K. Autosomal genes in male infertility. In: Male infertility: understanding, causes treat. Springer; 2017. pp 231–252.

  27. Jedidi I, Ouchari M, Yin Q. Autosomal single-gene disorders involved in human infertility. Saudi J Biol Sci. 2018;25:881–7.

    Article  CAS  PubMed  Google Scholar 

  28. Seidel MG, Duerr C, Woutsas S, Schwerin-Nagel A, Sadeghi K, Neesen J, et al. A novel immunodeficiency syndrome associated with partial trisomy 19p13. J Med Genet. 2014;51:254–63 jmedgenet-2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Xia Z, Zheng X, Zheng H, Liu X, Yang Z, Wang X. Cold-inducible RNA-binding protein (CIRP) regulates target mRNA stabilization in the mouse testis. FEBS Lett. 2012;586:3299–308.

    Article  CAS  PubMed  Google Scholar 

  30. Xia Y, Sidis Y, Schneyer A. Overexpression of follistatin-like 3 in gonads causes defects in gonadal development and function in transgenic mice. Mol Endocrinol. 2004;18:979–94.

    Article  CAS  PubMed  Google Scholar 

  31. Oldknow KJ, Seebacher J, Goswami T, Villen J, Pitsillides AA, O’shaughnessy PJ, et al. Follistatin-like 3 (FSTL3) mediated silencing of transforming growth factor β (TGFβ) signaling is essential for testicular aging and regulating testis size. Endocrinology. 2013;154:1310–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schneider M, Förster H, Boersma A, Seiler A, Wehnes H, Sinowatz F, et al. Mitochondrial glutathione peroxidase 4 disruption causes male infertility. FASEB J. 2009;23:3233–42.

    Article  CAS  PubMed  Google Scholar 

  33. Schmidt A, Marescau B, Boehm EA, Renema WKJ, Peco R, Das A, et al. Severely altered guanidino compound levels, disturbed body weight homeostasis and impaired fertility in a mouse model of guanidinoacetate N-methyltransferase (GAMT) deficiency. Hum Mol Genet. 2004;13:905–21.

    Article  CAS  PubMed  Google Scholar 

  34. Clarke H, Dhillo WS, Jayasena CN. Comprehensive review on kisspeptin and its role in reproductive disorders. Endocrinol Metab. 2015;30:124–41.

    Article  CAS  Google Scholar 

  35. Kong F, Wang M, Huang X, Yue Q, Wei X, Dou X, et al. Differential regulation of spermatogenic process by Lkb1 isoforms in mouse testis. Cell Death Dis. 2017;8:e3121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gyamera-Acheampong C, Tantibhedhyangkul J, Weerachatyanukul W, Tadros H, Xu H, van de Loo J-W, et al. Sperm from mice genetically deficient for the PCSK4 proteinase exhibit accelerated capacitation, precocious acrosome reaction, reduced binding to egg zona pellucida, and impaired fertilizing ability. Biol Reprod. 2006;74:666–73.

    Article  CAS  PubMed  Google Scholar 

  37. Mbikay M, Tadros H, Ishida N, Lerner CP, De Lamirande E, Chen A, et al. Impaired fertility in mice deficient for the testicular germ-cell protease PC4. Proc Natl Acad Sci. 1997;94:6842–6.

    Article  CAS  PubMed  Google Scholar 

  38. Johansson MM, Van Geystelen A, Larmuseau MHD, Djurovic S, Andreassen OA, Agartz I, et al. Microarray analysis of copy number variants on the human Y chromosome reveals novel and frequent duplications overrepresented in specific haplogroups. PLoS One. 2015;10:e0137223.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Connallon T, Clark AG. Gene duplication, gene conversion, and the evolution of the Y chromosome. Genetics. 2010;186:277–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors thank the patients for providing blood samples and their consent for genetic analysis. We would like to acknowledge the Interdisciplinary School of Life Sciences (ISLS), Banaras Hindu University for Affymetrix Microarray Facility. The first author thanks CSIR for the Senior Research Fellowship.

Funding

The study was funded by the Board of Research in Nuclear Sciences (BRNS), Govt. of India, with sanction number 2013/37B/27/BRNS.

Author information

Authors and Affiliations

  1. Department of Molecular & Human Genetics, Banaras Hindu University, Varanasi, 221005, India

    Vertika Singh, Renu Bala, Arijit Chakraborty & Kiran Singh

  2. Division of Endocrinology, Central Drug Research Institute, Lucknow, India

    Singh Rajender

  3. Department of Urology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India

    Sameer Trivedi

Authors
  1. Vertika Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Renu Bala
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arijit Chakraborty
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Singh Rajender
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sameer Trivedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kiran Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kiran Singh.

Ethics declarations

This study was approved by the Institutional Human Ethics Committee of the Institute of Science, Banaras Hindu University, Varanasi, approved this study (Approval letter No. Dean/2011-12/119).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee.

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

a Microarray results for 19p13.3 duplication using CytoScan™ 750K Array (Affymetrix, USA). Analysis using the ChAS software (Affymetrix, USA) showed a common genomic gain at the 19p13.3 region in 9 (26.47%) cases (P1 to P9). The locus and extent of duplication in all the nine cases are represented by bold blue lines. For comparison, one control (CONTROL2) is used which shows an absence of duplication. b Representative microarray profile of patient with the largest 19p13.3 duplication in comparison with that of the control. The dots indicate individual markers in that region. Genomic gain is detected as an increase in the weighted log2 ratio and copy number state. The lower lines show the copy number in both cases (PNG 16.1 mb)

High Resolution Image (TIF 16.7 mb)

ESM 2

Graphical representation of cnLOH at the 3p21.31 region observed in 6 (17.6%) of the cases by ChAS software (Affymetrix, USA). Further, the software was set to a cutoff of ≥ 5 Mb for displaying loss of heterozygosity. The extent of cnLOH is represented using bold purple lines. For comparison, one control is represented showing absence of cnLOH (PNG 2.50 mb)

High Resolution Image (TIF 24.6 mb)

ESM 3

(PDF 569 kb)

ESM 4

(PDF 227 kb)

ESM 5

(XLSX 26 kb)

ESM 6

(XLSX 9 kb)

ESM 7

(PDF 286 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Singh, V., Bala, R., Chakraborty, A. et al. Duplications in 19p13.3 are associated with male infertility. J Assist Reprod Genet 36, 2171–2179 (2019). https://doi.org/10.1007/s10815-019-01547-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-019-01547-1

Keywords

Search

Navigation