Increasing associations between defects in phospholipase C zeta and conditions of male infertility: not just ICSI failure?



Oocyte activation is a fundamental event at mammalian fertilization. In mammals, this process is initiated by a series of characteristic calcium (Ca2+) oscillations, induced by a sperm-specific phospholipase C (PLC) termed PLCzeta (PLCζ). Dysfunction/reduction/deletion of PLCζ is associated with forms of male infertility where the sperm is unable to initiate Ca2+ oscillations and oocyte activation, specifically in cases of fertilization failure. This review article aims to systematically summarize recent advancements and controversies in the field to update expanding clinical associations between PLCζ and various male factor conditions. This article also discusses how such associations may potentially underlie defective embryogenesis and recurrent implantation failure following fertility treatments, alongside potential diagnostic and therapeutic PLCζ approaches, aiming to direct future research efforts to utilize such knowledge clinically.


An extensive literature search was performed using literature databases (PubMed/MEDLINE/Web of Knowledge) focusing on phospholipase C zeta (PLCzeta; PLCζ), oocyte activation, and calcium oscillations, as well as specific male factor conditions.

Results and discussion

Defective PLCζ or PLCζ-induced Ca2+ release can be linked to multiple forms of male infertility including abnormal sperm parameters and morphology, sperm DNA fragmentation and oxidation, and abnormal embryogenesis/pregnancies. Such sperm exhibit absent/reduced levels, and abnormal localization patterns of PLCζ within the sperm head.


Defective PLCζ and abnormal patterns of Ca2+ release are increasingly suspected a significant causative factor underlying abnormalities or insufficiencies in Ca2+ oscillation-driven early embryogenic events. Such cases could potentially strongly benefit from relevant therapeutic and diagnostic applications of PLCζ, or even alternative mechanisms, following further focused research efforts.

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JK was supported by a Healthcare Research Fellowship Award (HF-14-16) made by Health and Care Research Wales (HCRW), alongside a National Science, Technology, and Innovation plan (NSTIP) project grant (15-MED4186-20) awarded by the King Abdulaziz City for Science and Technology (KACST).

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JK conceived, planned, and collated studies for this article, and wrote the final manuscript.

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Correspondence to Junaid Kashir.

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Ethics statement approval of research involving regulated animals

Use of mouse and human sperm cells was performed in accordance with the principles of the Basel Declaration and recommendations of the Animal Care and Use Committee (ACUC) at the Office of Research Affairs (ORA) at the King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia. The protocols utilized for the relevant studies (RAC-2160014 and 2160015) were approved by the ACUC. For the involvement of human subjects, samples were only obtained following informed written consent, and were performed according to the Declaration of Helsinki.

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Kashir, J. Increasing associations between defects in phospholipase C zeta and conditions of male infertility: not just ICSI failure?. J Assist Reprod Genet 37, 1273–1293 (2020).

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  • Phospholipase C zeta (PLCzeta)
  • Oocyte activation
  • Fertilization: Sperm
  • Infertility: Assisted reproductive technology