ArticleAmerican journal of human genetics2021
Homozygous pathogenic variants in ACTL9 cause fertilization failure and male infertility in humans and mice.
Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers, 1 of them a synthesis that pooled it.
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Who cites it
42 citing papers in PubMed, 1 synthesis or guideline pooled it, 84 citations in OpenAlex.
- Assessing the impact of calcium ionophore on pregnancy outcomes in artificial oocyte activation cycles: a 10-year update of systematic review and meta-analysis.Journal of assisted reproduction and genetics · 2025Pooled it
- A comprehensive review for defining cut-off values of oocyte, zygote, and embryo maturation arrest (OZEMA) due to maternal-effect genes: towards the establishment of clinical criteria.Human reproduction (Oxford, England) · 2026Review
- Characterization and therapy of fertilization failure in murine and human models with HNRNPR mutations.EMBO molecular medicine · 2026Article
- Protein disulfide isomerase A6 (PDIA6) is essential for acrosome biogenesis and male fertility in mice.Cell communication and signaling : CCS · 2026Article
- Meiotic gene variants contribute to recurrent blastulation failure.Human reproduction open · 2026Article
- Precise mimicry of physiological CaBioengineering & translational medicine · 2026Article
- A Novel Variant of theGenes · 2025Article
- Mutational disruption of transcription factors binding and regulatory networks in a case of unexplained total fertilization failure.Journal of translational medicine · 2025Article
- Novel CYLC1 variants are associated with male infertility due to sperm head deformity.Journal of assisted reproduction and genetics · 2025Article
- Of mice and men: translating mouse knockout models of human male infertility.Reproduction (Cambridge, England) · 2025Review
- Article
- Identification of nonfunctional CABS1 causing fertilization failure and male infertility in humans: a case report.Journal of assisted reproduction and genetics · 2025Article
- Phospholipases: Paving the Way for a New Life.Reproductive sciences (Thousand Oaks, Calif.) · 2025Review
- Sperm-Derived Dysfunction of Human Embryos: Molecular Mechanisms and Clinical Resolution.International journal of molecular sciences · 2025Review
- Article
- Dnajc5b contributes to male fertility by maintaining the mitochondrial functions and autophagic homeostasis during spermiogenesis.Cellular and molecular life sciences : CMLS · 2025Article
- Advances in the genetic etiology of female infertility.Journal of assisted reproduction and genetics · 2024Review
- Homozygous ACTL9 mutations cause irregular mitochondrial sheath arrangement and abnormal flagellum assembly in spermatozoa and male infertility.Journal of assisted reproduction and genetics · 2024Article
- Conserved genes regulating human sex differentiation, gametogenesis and fertilization.Journal of translational medicine · 2024Review
- Identification of a new mutation in the ACTL9 gene in men with unexplained infertility.Molecular genetics & genomic medicine · 2024Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Total fertilization failure (TFF) can occur during in vitro fertilization (IVF) treatments, even following intracytoplasmic sperm injection (ICSI). Various male or female factors could contribute to TFF. Increasing evidence suggested that genetic variations in PLCZ1, which encodes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1 (PLCζ), is involved in oocyte activation and is a key male factor in TFF. In the present study, we explored the genetic variants in male individuals that led to TFF. A total of 54 couples with TFF or poor fertilization (fertilization rate < 20%) were screened, and 21 couples were determined to have a male infertility factor by the mouse oocyte activation test. Whole-exome sequencing of these 21 male individuals identified three homozygous pathogenic variants in ACTL9 (actin like 9) in three individuals. ACTL9 variations led to abnormal ultrastructure of the perinuclear theca (PT), and PLCζ was absent in the head and present in the neck of the mutant sperm, which contributed to failed normal calcium oscillations in oocytes and subsequent TFF. The key roles of ACTL9 in the PT structure and TFF after ICSI were further confirmed in an Actl9-mutated mouse model. Furthermore, assisted oocyte activation by calcium ionophore exposure successfully overcame TFF and achieved live births in a couple with an ACTL9 variant. These findings identified the role of ACTL9 in the PT structure and the correct localization of PLCζ. The results also provide a genetic marker and a therapeutic option for individuals who have undergone ICSI without successful fertilization.
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