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Biallelic variants in α-tubulin isotypes cause female infertility characterised as recurrent preimplantation embryo arrest.
- Source :
-
Journal of medical genetics [J Med Genet] 2024 Oct 23; Vol. 61 (11), pp. 1045-1052. Date of Electronic Publication: 2024 Oct 23. - Publication Year :
- 2024
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Abstract
- Background: Recurrent preimplantation embryo developmental arrest (RPEA) is the most common phenotype in assisted reproductive technology treatment failure associated with identified genetic abnormalities. Currently known maternal genetic variants explain only a limited number of cases. Variants of the β-tubulin subunit gene, TUBB8 , cause oocyte meiotic arrest and RPEA through a broad spectrum of spindle defects. In contrast, α-tubulin subunit genes are poorly studied in the context of preimplantation embryonic development.<br />Methods: Whole exome sequencing was performed on the PREA cohort. Functional characterisations of the identified candidate disease-causing variants were validated using Sanger sequencing, bioinformatics, in vitro functional analyses and single-cell RNA-sequencing of arrested embryos.<br />Results: Four homozygous variants were identified in the PREA cohort: two of TUBA1C (p.Gln358Ter and p.Asp444Metfs*42) and two of TUBA4A (p.Arg339Cys and p.Tyr440Ter). These variants cause varying degrees of spindle assembly defects. Additionally, we characterised changes in the human arrested embryo transcriptome carrying TUBA4A variants, with a particular focus on spindle organisation, chromosome segregation and mRNA decay.<br />Conclusion: Our findings identified TUBA1C as a novel genetic marker and expanded the genetic and phenotypic spectrum of TUBA4A in female infertility and RPEA, which altogether highlighted the importance of α-tubulin isotypes in preimplantation embryonic development.<br />Competing Interests: Competing interests: None declared.<br /> (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
Details
- Language :
- English
- ISSN :
- 1468-6244
- Volume :
- 61
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of medical genetics
- Publication Type :
- Academic Journal
- Accession number :
- 39209701
- Full Text :
- https://doi.org/10.1136/jmg-2024-110163