Mutations in genes affecting fertility of men – current routine laboratory genetic diagnostics and searching for more DNA segments and genes influencing spermatogenesis

Česká verzia

Authors: I. Hrdlička ¹; B. Chylíková ¹; K. Veselá ¹; M. Daňková ¹; M. Janků ¹; K. Řežábek ²; R. Mihalová ¹; F. Liška ¹
Authors place of work: Ústav biologie a lékařské genetiky 1. LF UK a VFN, Praha, přednostka doc. MUDr. M. Kohoutová, CSc. ¹; Gynekologicko-porodnická klinika 1. LF UK a VFN, Praha, přednosta prof. MUDr. A. Martan, DrSc. ²
Published in the journal: Ceska Gynekol 2016; 81(6): 437-443

Summary

Objective:
To present the results of molecular genetics analysis in men with reproductive disorders focusing on the DNA segments and genes which affect spermatogenesis.

Design:
Original article.

Setting:
Institute of Biology and Medical Genetics of the First Faculty of Medicine and General Teaching Hospital, Prague.

Methods:
One hundred and twenty-three patients identified with a fertility disorder were screened for mutations of the CFTR gene. In all patients were performed cytogenic analysis and assessment of Y-chromosome microdeletions. In 107 patients where the fertility was not detected by routine examination we performed an analysis for X-chromosome microdeletions (CNV64, CNV67, CNV69) and in certain genes necessary for normal spermatogenesis (AGFG1, CAPZA3, CNTROB, HOOK1, GOPC, SPATA16).

Results:
Our results did not reveal any negative efffects of X-chromosome microdeletion on spermatogenesis. Analysis of six genes showed in two patients in gene SPATA16 a homozygotic haplotype [1526C>T + 1577T>C] which can be most probably responsible for the fertility in two examined patients.

Conclusion:
According to our results we do not recommend introduction of X-chromosome microdeletions assays in areas CNV64 , CNV67 and CNV69 into routine diagnostic. Regarding the selected genes affecting spermatogenesis, our results showed that homozygotic haplotype [ 1526C>T + 1577T>C] in SPATA16 gene is very likely responsible for infertility in two of our patients. The above mentioned haplotype deserves attention in the investigation of male infertility.

Keywords:
male infertility, X-chromosome microdeletions, AGFG1 gene, CAPZA3 gene, CNTROB gene, HOOK1 gene, GOPC gene, SPATA16 gene

Zdroje

1. Adzhubei, IA., Schmidt, S., Peshkin, L., et al. A method and server for predicting damaging missense mutations. Nat Methods, 2010, 7, p. 248–249.

2. Behre, HM., Bergmann, M., Simoni, M., Tüttelmann, F. Primary testicular failure. In: De Groot, LJ., Beck-Peccoz, P., Chrousos, G., et al., eds. Source Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–2015 Aug 30.

3. Bult, CJ., Eppig, JT., Blake, JA., et al. Mouse Genome Database 2016. Nucleic Acids Res, 2016, 44(D1):D840–7. Epub 2015 Nov 17.

4. Castellani, C., Cuppens, H., Macek, M. Jr., et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros, 2008, 7, p. 179–196.

5. Dam, AH., Koscinski, I., Kremer, JA., et al. Homozygous mutation in SPATA16 is associated with male infertility in human globozoospermia. Am J Hum Genet, 2007, 81, p. 813–820.

6. Geyer, CB., Inselman, AL., Sunman, JA., et al. A missense mutation in the Capza3 gene and disruption of F-actin organization in spermatids of repro32 infertile male mice. Dev Biol, 2009, 330, p. 142–152.

7. Hrdlička, I. Problematika interpretace výsledků molekulárně genetických vyšetření se zaměřením na mutace v CFTR genu u mužů s poruchami reprodukce a u dárců/dárkyň gamet. Čes Gynek, 2008, 73, 6, s. 323–327.

8. Choi, Y., Sims, GE., Murphy, S., et al. Predicting the functional effect of amino acid substitutions and indels. PLoS One, 2012, 7, e46688.

9. Chylíková, B., Hrdlička, I., Veselá, K., et al. Recurrent microdeletions at Xq27.3-Xq28 and male infertility: a study in the Czech population. PLoS ONE, 2016, 11(6), e0156102.

10. Kierszenbaum, AL., Tres, LL., Rivkin, E., et al. The acroplaxome is the docking site of Golgi-derived myosin Va/Rab27a/b- containing proacrosomal vesicles in wild-type and Hrb mutant mouse spermatids. Biol Reprod, 2004, 70, p. 1400–1410.

11. Krausz, C., Giachini C., Lo Giacco D., Daguin, F., et al. High Resolution X Chromosome-Specific Array-CGH Detects New CNVs in Infertile Males. PLoS One, 2012, 7(10): e44887.

12. Liška, F. Selected genetic aspects of male infertility – what animal models tell us. Folia Biol (Praha), 2003, 49, p. 129–141.

13. Liska, F., Gosele, C., Rivkin, E., et al. Rat hd mutation reveals an essential role of centrobin in spermatid head shaping and assembly of the head-tail coupling apparatus. Biol Reprod, 2009, 81, p. 1196-1205.

14. Lo Giacco, D., Chianese, C., Ars, E., et al. Recurrent X chromosome-linked deletions: discovery of new genetic factors in male infertility. J Med Genet, 2014, 51, p. 340–344.

15. Maldonado-Baez, L., Cole, NB., Kramer, H., Donaldson, JG. Microtubuledependent endosomal sorting of clathrin-independent cargo by Hook1. J Cell Biol, 2013, 201, p. 233–247.

16. Massart, A., Lissens, W., Tournaye, H., Stouffs, K. Genetic causes of spermatogenic failure. Asian J Androl, 2012, 14, p. 40–48.

17. Matzuk, MM., Lamb, DJ. The biology of infertility: research advances and clinical challenges. Nat Med, 2008, 14, p. 1197–1213.

18. Mendoza-Lujambio, I., Burfeind, P., Dixkens, C., et al. The Hook1 gene is non-functional in the abnormal spermatozoon head shape (azh) mutant mouse. Hum Mol Genet, 2002, 11, p. 1647–1658.

19. Ng, PC., Henikoff, S. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res, 2003, 31, p. 3812–3814.

20. Simoni, M., Bakker, E., Krausz, C. EAA/EMQN best practice guidelines for molecular diagnosis of y-chromosomal microdeletions. State of the art 2004. Int J Androl, 2004, 27, p. 240–249.

21. Suzuki-Toyota, F., Ito, C., Toyama, Y., et al. Factors maintaining normal sperm tail structure during epididymal maturation studied in Gopc-/- mice. Biol reprod, 2007, 77, p. 71–82.

22. Wang, Y., Liska, F., Gosele, C., et al. A novel active endogenous retrovirus family contributes to genome variability in rat inbred strains. Genome Res, 2010, 20, p. 19–27.

23. Yu, XW., Wei, ZT., Jiang, YT., Zhang, SL. Y chromosome azoospermia factor region microdeletions and transmission characteristics in azoospermic and severe oligozoospermic patients. Int J Clin Exp Med, 2015, 8, p. 14634–14646.

24. Yao, R., Ito, C., Natsume, Y., et al. Lack of acrosome formation in mice lacking a Golgi protein, GOPC. Proc Natl Acad Sci USA, 2002, 99, p. 11211–11216.