A novel PLCζ mutation linked to male factor infertility induces a gain-of-function effect on Ca2+ oscillations in eggs

Saleh, Alaaeldin, Huang, Zizhen, Al Shaikh, Maryam, Jurkowski, Tomasz P. ORCID: https://orcid.org/0000-0002-2012-0240, Islam, Zeyaul, Swann, Karl and Nomikos, Michail 2025. A novel PLCζ mutation linked to male factor infertility induces a gain-of-function effect on Ca2+ oscillations in eggs. International Journal of Molecular Sciences 26 (13) , 6241. 10.3390/ijms26136241

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Abstract

Mammalian fertilization is triggered by a series of calcium (Ca2+) oscillations that are essential for egg activation and successful embryo development. It is widely accepted that Phospholipase C zeta (PLCζ) is the sperm-derived factor that triggers these oscillations, initiating egg activation through the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), leading to Ca2+ release. Several studies have reported a number of PLCζ mutations associated with polyspermy, egg activation failure and early embryonic arrest. Herein, six infertility-linked PLCζ mutations (I120M, L246F, L277P, S350P, A384V and M578T) spanning different domains of PLCζ were selected for characterization through in vivo assessment of their Ca2+-oscillation-inducing activities and complementary in silico analysis. Our data revealed that five of the investigated PLCζ mutants exhibited reduced or complete loss of in vivo Ca2+-oscillation-inducing activity, with the exception of the L277P, which resulted in increased frequency and duration of Ca2+ oscillations. Molecular modeling of PLCζ mutants was consistent with the in vivo characterization, revealing that most mutations have a deleterious effect on the structural stability. For the first time, we provide evidence that a gain-of-function PLCζ mutation may be a cause of fertilization failure in humans. Our findings suggest that PLCζ enzymatic activity must operate within an optimal range to ensure successful egg activation and early embryonic development. Additionally, we demonstrate the essential role of all PLCζ domains in maintaining the Ca2+ oscillation-inducing activity in eggs and the importance of PLCζ functionality in human fertilization.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Biosciences
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by/4.0/, Start Date: 2025-06-28
Publisher:	MDPI
ISSN:	1661-6596
Date of First Compliant Deposit:	16 July 2025
Date of Acceptance:	27 June 2025
Last Modified:	16 Jul 2025 09:45
URI:	https://orca.cardiff.ac.uk/id/eprint/179860

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