{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T10:05:05Z","timestamp":1788861905653,"version":"build-2803163510"},"reference-count":53,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,28]],"date-time":"2025-06-28T00:00:00Z","timestamp":1751068800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Qatar Research Development and Innovation Council (QRDI)","award":["NPRP-BSRA1-0504-210082"],"award-info":[{"award-number":["NPRP-BSRA1-0504-210082"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 (PLC\u03b6) 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 PLC\u03b6 mutations associated with polyspermy, egg activation failure and early embryonic arrest. Herein, six infertility-linked PLC\u03b6 mutations (I120M, L246F, L277P, S350P, A384V and M578T) spanning different domains of PLC\u03b6 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 PLC\u03b6 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 PLC\u03b6 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 PLC\u03b6 mutation may be a cause of fertilization failure in humans. Our findings suggest that PLC\u03b6 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 PLC\u03b6 domains in maintaining the Ca2+ oscillation-inducing activity in eggs and the importance of PLC\u03b6 functionality in human fertilization.<\/jats:p>","DOI":"10.3390\/ijms26136241","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T05:28:28Z","timestamp":1751347708000},"page":"6241","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Novel PLC\u03b6 Mutation Linked to Male Factor Infertility Induces a Gain-of-Function Effect on Ca2+ Oscillations in Eggs"],"prefix":"10.3390","volume":"26","author":[{"given":"Alaaeldin","family":"Saleh","sequence":"first","affiliation":[{"name":"Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha P.O. Box 123, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3665-4557","authenticated-orcid":false,"given":"Zizhen","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6843-8062","authenticated-orcid":false,"given":"Maryam","family":"Al Shaikh","sequence":"additional","affiliation":[{"name":"School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz P.","family":"Jurkowski","sequence":"additional","affiliation":[{"name":"School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5444-3910","authenticated-orcid":false,"given":"Zeyaul","family":"Islam","sequence":"additional","affiliation":[{"name":"Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Doha P.O. Box 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Swann","sequence":"additional","affiliation":[{"name":"School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michail","family":"Nomikos","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha P.O. Box 123, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nrm3643","article-title":"Restarting life: Fertilization and the transition from meiosis to mitosis","volume":"14","author":"Clift","year":"2013","journal-title":"Nat. Rev. Mol. 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