Biallelic variants in α-tubulin isotypes cause female infertility characterised as recurrent preimplantation embryo arrest.
J Med Genet
; 2024 Aug 29.
Article
en En
| MEDLINE
| ID: mdl-39209701
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 ß-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.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.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.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.
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MEDLINE
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En
Revista:
J Med Genet
Año:
2024
Tipo del documento:
Article
País de afiliación:
China