Mutations in the Prostate Specific Antigen (PSA/KLK3) Correlate with Male Infertility

Overview

Journal Sci Rep

Specialty Science

Date 2017 Sep 13

PMID 28894123

Citations 9

Authors

Nishi Gupta

Digumarthi V S Sudhakar

Pravin Kumar Gangwar

Satya Narayan Sankhwar

Nalini J Gupta

Baidyanath Chakraborty

Kumarasamy Thangaraj

Gopal Gupta

Singh Rajender

Affiliations

Soon will be listed here.

Abstract

Prostate specific antigen (PSA/KLK3) is known to be the chief executor of the fragmentation of semenogelins, dissolution of semen coagulum, thereby releasing sperm for active motility. Recent research has found that semenogelins also play significant roles in sperm fertility by affecting hyaluronidase activity, capacitation and motility, thereby making PSA important for sperm fertility beyond simple semen liquefaction. PSA level in semen has been shown to correlate with sperm motility, suggesting that PSA level/activity can affect fertility. However, no study investigating the genetic variations in the KLK3/PSA gene in male fertility has been undertaken. We analyzed the complete coding region of the KLK3 gene in ethnically matched 875 infertile and 290 fertile men to find if genetic variations in KLK3 correlate with infertility. Interestingly, this study identified 28 substitutions, of which 8 were novel (not available in public databases). Statistical comparison of the genotype frequencies showed that five SNPs, rs266881 (OR = 2.92, P < 0.0001), rs174776 (OR = 1.91, P < 0.0001), rs266875 (OR = 1.44, P = 0.016), rs35192866 (OR = 4.48, P = 0.025) and rs1810020 (OR = 2.08, P = 0.034) correlated with an increased risk of infertility. On the other hand, c.206 + 235 T > C, was more freuqent in the control group, showing protective association. Our findings suggest that polymorphisms in the KLK3 gene correlate with infertility risk.

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References

Veveris-Lowe T, Kruger S, Walsh T, Gardiner R, Clements J . Seminal fluid characterization for male fertility and prostate cancer: kallikrein-related serine proteases and whole proteome approaches. Semin Thromb Hemost. 2007; 33(1):87-99. DOI: 10.1055/s-2006-958467. View

Marques P, Fonseca F, Carvalho A, Puente D, Damiao I, Almeida V . Sequence variation at KLK and WFDC clusters and its association to semen hyperviscosity and other male infertility phenotypes. Hum Reprod. 2016; 31(12):2881-2891. DOI: 10.1093/humrep/dew267. View

Kumar A, Mikolajczyk S, Goel A, Millar L, Saedi M . Expression of pro form of prostate-specific antigen by mammalian cells and its conversion to mature, active form by human kallikrein 2. Cancer Res. 1997; 57(15):3111-4. View

Ahlgren G, Rannevik G, Lilja H . Impaired secretory function of the prostate in men with oligo-asthenozoospermia. J Androl. 1995; 16(6):491-8. View

Shaw J, Diamandis E . Distribution of 15 human kallikreins in tissues and biological fluids. Clin Chem. 2007; 53(8):1423-32. DOI: 10.1373/clinchem.2007.088104. View

Robert M, Gagnon C . Semenogelin I: a coagulum forming, multifunctional seminal vesicle protein. Cell Mol Life Sci. 1999; 55(6-7):944-60. PMC: 11146994. DOI: 10.1007/s000180050346. View

Yoshida K, Kawano N, Yoshiike M, Yoshida M, Iwamoto T, Morisawa M . Physiological roles of semenogelin I and zinc in sperm motility and semen coagulation on ejaculation in humans. Mol Hum Reprod. 2008; 14(3):151-6. DOI: 10.1093/molehr/gan003. View

Mandal A, Bhattacharyya A . Sperm hyaluronidase activation by purified predominant and major basic human seminal coagulum proteins. Hum Reprod. 1995; 10(7):1745-50. DOI: 10.1093/oxfordjournals.humrep.a136167. View

Robert M, Gagnon C . Sperm motility inhibitor from human seminal plasma: association with semen coagulum. Hum Reprod. 1995; 10(8):2192-7. DOI: 10.1093/oxfordjournals.humrep.a136267. View

10.

Jonsson M, Linse S, Frohm B, Lundwall A, Malm J . Semenogelins I and II bind zinc and regulate the activity of prostate-specific antigen. Biochem J. 2004; 387(Pt 2):447-53. PMC: 1134973. DOI: 10.1042/BJ20041424. View

11.

Kumar V, Hassan M, Kashav T, Singh T, Yadav S . Heparin-binding proteins of human seminal plasma: purification and characterization. Mol Reprod Dev. 2008; 75(12):1767-74. DOI: 10.1002/mrd.20910. View

12.

Jia L, Coetzee G . Androgen receptor-dependent PSA expression in androgen-independent prostate cancer cells does not involve androgen receptor occupancy of the PSA locus. Cancer Res. 2005; 65(17):8003-8. DOI: 10.1158/0008-5472.CAN-04-3679. View

13.

Robert M, Gagnon C . Purification and characterization of the active precursor of a human sperm motility inhibitor secreted by the seminal vesicles: identity with semenogelin. Biol Reprod. 1996; 55(4):813-21. DOI: 10.1095/biolreprod55.4.813. View

14.

Christensson A, LAURELL C, Lilja H . Enzymatic activity of prostate-specific antigen and its reactions with extracellular serine proteinase inhibitors. Eur J Biochem. 1990; 194(3):755-63. DOI: 10.1111/j.1432-1033.1990.tb19466.x. View

15.

Lee S, Lee S . Genetic association study of a single nucleotide polymorphism of kallikrein-related peptidase 2 with male infertility. Clin Exp Reprod Med. 2012; 38(1):6-9. PMC: 3283048. DOI: 10.5653/cerm.2011.38.1.6. View

16.

Muytjens C, Vasiliou S, Oikonomopoulou K, Prassas I, Diamandis E . Putative functions of tissue kallikrein-related peptidases in vaginal fluid. Nat Rev Urol. 2016; 13(10):596-607. DOI: 10.1038/nrurol.2016.161. View

17.

Yoshida K, Krasznai Z, Krasznai Z, Yoshiike M, Kawano N, Yoshida M . Functional implications of membrane modification with semenogelins for inhibition of sperm motility in humans. Cell Motil Cytoskeleton. 2008; 66(2):99-108. DOI: 10.1002/cm.20329. View

18.

Thangaraj K, Joshi M, Reddy A, Gupta N, Chakravarty B, Singh L . CAG repeat expansion in the androgen receptor gene is not associated with male infertility in Indian populations. J Androl. 2002; 23(6):815-8. View

19.

Wang Z, Widgren E, Richardson R, ORand M . Characterization of an eppin protein complex from human semen and spermatozoa. Biol Reprod. 2007; 77(3):476-84. DOI: 10.1095/biolreprod.107.060194. View

20.

Akiyama K, Nakamura T, Iwanaga S, Hara M . The chymotrypsin-like activity of human prostate-specific antigen, gamma-seminoprotein. FEBS Lett. 1987; 225(1-2):168-72. DOI: 10.1016/0014-5793(87)81151-1. View