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Hum. Reprod. Advance Access published online on July 7, 2009
Human Reproduction, doi:10.1093/humrep/dep207
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© The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Reduced amounts and abnormal forms of phospholipase C zeta (PLC{zeta}) in spermatozoa from infertile men

E. Heytens1,{dagger}, J. Parrington2,{dagger}, K. Coward2,3, C. Young2, S. Lambrecht5, S.-Y. Yoon4, R.A. Fissore4, R. Hamer5, C.M. Deane6, M. Ruas2, P. Grasa2, R. Soleimani1, C.A. Cuvelier7, J. Gerris1, M. Dhont1, D. Deforce5, L. Leybaert8,{ddagger} and P. De Sutter1,{ddagger},9

1 Department of Reproductive Medicine, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium 2 Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK 3 Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Level 3 Women's Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK 4 Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, USA 5 Laboratory of Pharmaceutical Biotechnology, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium 6 Department of Statistics, University of Oxford, South Parks Road, Oxford OX1 3TG, UK 7 Department of Pathology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium 8 Department of Basic Medical Sciences, Physiology Group, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium

9Correspondence address. E-mail: petra.desutter{at}ugent.be

BACKGROUND: In mammals, oocyte activation at fertilization is thought to be induced by the sperm-specific phospholipase C zeta (PLC{zeta}). However, it still remains to be conclusively shown that PLC{zeta} is the endogenous agent of oocyte activation. Some types of human infertility appear to be caused by failure of the sperm to activate and this may be due to specific defects in PLC{zeta}.

METHODS AND RESULTS: Immunofluorescence studies showed PLC{zeta} to be localized in the equatorial region of sperm from fertile men, but sperm deficient in oocyte activation exhibited no specific signal in this same region. Immunoblot analysis revealed reduced amounts of PLC{zeta} in sperm from infertile men, and in some cases, the presence of an abnormally low molecular weight form of PLC{zeta}. In one non-globozoospermic case, DNA analysis identified a point mutation in the PLC{zeta} gene that leads to a significant amino acid change in the catalytic region of the protein. Structural modelling suggested that this defect may have important effects upon the structure and function of the PLC{zeta} protein. cRNA corresponding to mutant PLC{zeta} failed to induce calcium oscillations when microinjected into mouse oocytes. Injection of infertile human sperm into mouse oocytes failed to activate the oocyte or trigger calcium oscillations. Injection of such infertile sperm followed by two calcium pulses, induced by assisted oocyte activation, activated the oocytes without inducing the typical pattern of calcium oscillations.

CONCLUSIONS: Our findings illustrate the importance of PLC{zeta} during fertilization and suggest that mutant forms of PLC{zeta} may underlie certain types of human male infertility.

Key words: PLC{zeta}/infertility/sperm/globozoospermia/oocyte activation

{dagger} Contributed equally to this work.

{ddagger} Shared senior authorship.

Submitted on March 3, 2009; resubmitted on May 1, 2009; accepted on May 13, 2009.


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