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

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. 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. 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.