ArticleHuman molecular genetics2016
Homozygous mutation of PLCZ1 leads to defective human oocyte activation and infertility that is not rescued by the WW-binding protein PAWP.
Article in Human molecular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT07684339 (Assessing the Correlation Between Phospholipase C Zeta), which is not on this map. Cited by 76 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Assessing the Correlation Between Phospholipase C Zeta (PLCZeta) Measurements and Semen Parameters
Who cites it
76 citing papers in PubMed, 2 syntheses or guidelines pooled it, 143 citations in OpenAlex.
- Clinical Applications of Assisted Oocyte Activation in Couples with Various Reproductive Problems: A Systematic Review.Reproductive sciences (Thousand Oaks, Calif.) · 2024Pooled it
- Phospholipase C Zeta in Human Spermatozoa: A Systematic Review on Current Development and Clinical Application.International journal of molecular sciences · 2024Pooled it
- A catalytically competent sperm PLCzeta variant causes fertilization failure through protein insufficiency.Journal of assisted reproduction and genetics · 2026Article
- The importance of integrating genetic testing into reproductive medicine: a retrospective observational study investigating the monogenic causes of human infertility in couples considering ICSI.Journal of human genetics · 2026Observational
- Novel biallelic DNHD1 variants associated with male infertility with severe MMAF phenotype.Asian journal of andrology · 2026Article
- A comprehensive review about sperm-oocyte interactions and key activation factors of fertilization in mammals.The Canadian journal of urology · 2026Review
- Pathogenic homozygous PLCZ1 mutation reduces sperm protein levels with a simulated reduction of PIP2 binding: a case report.Reproduction & fertility · 2026Article
- Mutational disruption of transcription factors binding and regulatory networks in a case of unexplained total fertilization failure.Journal of translational medicine · 2025Article
- Obesity-Associated Discordance Between Sperm PLCζ mRNA Expression and Protein Localization in Men: A Preliminary Evaluation.Reproductive sciences (Thousand Oaks, Calif.) · 2025Article
- Effect of Sperm DNA Fragmentation and Chromatin Decondensation on PLCζ Efficacy in Infertile Patients.Current issues in molecular biology · 2025Article
- How exome sequencing improves the diagnostics and management of men with non-syndromic infertility.Andrology · 2025Review
- A Novel PLCζ Mutation Linked to Male Factor Infertility Induces a Gain-of-Function Effect on CaInternational journal of molecular sciences · 2025Article
- Phospholipase Cζ, the Molecular Spark of Fertilization and Male Infertility: Insights from Bench to Bedside.Medicina (Kaunas, Lithuania) · 2025Review
- Structural Implications of H233L and H398P Mutations in Phospholipase Cζ: A Full-Atom Molecular Dynamics Study on Infertility-Associated Dysfunctions.International journal of molecular sciences · 2025Article
- Novel PLCZ1 compound heterozygous mutations indicate gene dosage effect involved in total fertilisation failure after ICSI.Reproduction (Cambridge, England) · 2024Article
- Genetics of female and male infertility.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2024Article
- Phospholipase C zeta: a hidden face of sperm for oocyte activation and early embryonic development.Obstetrics & gynecology science · 2024Article
- Novel PLCZ1 mutation caused polyspermy during in vitro fertilization.Asian journal of andrology · 2024Article
- The mammalian sperm factor phospholipase C zeta is critical for early embryo division and pregnancy in humans and mice.Human reproduction (Oxford, England) · 2024Article
- Development of Recombinant PLC-Zeta Protein as a Therapeutic Intervention for the Clinical Treatment of Oocyte Activation Failure.Biomedicines · 2024Article
16 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 4 countries.
Funding
Abstract
In mammals, sperm-oocyte fusion initiates Ca(2+) oscillations leading to a series of events called oocyte activation, which is the first stage of embryo development. Ca(2+) signaling is elicited by the delivery of an oocyte-activating factor by the sperm. A sperm-specific phospholipase C (PLCZ1) has emerged as the likely candidate to induce oocyte activation. Recently, PAWP, a sperm-born tryptophan domain-binding protein coded by WBP2NL, was proposed to serve the same purpose. Here, we studied two infertile brothers exhibiting normal sperm morphology but complete fertilization failure after intracytoplasmic sperm injection. Whole exomic sequencing evidenced a missense homozygous mutation in PLCZ1, c.1465A>T; p.Ile489Phe, converting Ile 489 into Phe. We showed the mutation is deleterious, leading to the absence of the protein in sperm, mislocalization of the protein when injected in mouse GV and MII oocytes, highly abnormal Ca(2+) transients and early embryonic arrest. Altogether these alterations are consistent with our patients' sperm inability to induce oocyte activation and initiate embryo development. In contrast, no deleterious variants were identified in WBP2NL and PAWP presented normal expression and localization. Overall we demonstrate in humans, the absence of PLCZ1 alone is sufficient to prevent oocyte activation irrespective of the presence of PAWP. Additionally, it is the first mutation located in the C2 domain of PLCZ1, a domain involved in targeting proteins to cell membranes. This opens the door to structure-function studies to identify the conserved amino acids of the C2 domain that regulate the targeting of PLCZ1 and its selectivity for its lipid substrate(s).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.