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Genotype-phenotype correlations
Original research
Biallelic variants in α-tubulin isotypes cause female infertility characterised as recurrent preimplantation embryo arrest
  1. Huiling Hu1,2,3,
  2. Xian Wan4,
  3. Honghui Zhang5,
  4. Jiaqi Sun1,
  5. Fei Meng3,
  6. Shuoping Zhang3,
  7. Yifan Gu3,6,
  8. Fei Gong3,6,
  9. Han Zhao5,
  10. Ge Lin3,6,
  11. Wei Zheng1,3
  1. 1Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
  2. 2College of Life Science, Hunan Normal University, Changsha, Hunan, China
  3. 3Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha, Hunan, China
  4. 4The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
  5. 5Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shangdong, China
  6. 6NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
  1. Correspondence to Professor Wei Zheng, Central South University, Changsha, Hunan, China; ustczw{at}163.com; Dr Ge Lin; linggf{at}hotmail.com

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.

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.

  • Genetic Variation
  • Women's Health

Data availability statement

Data are available upon reasonable request. Not applicable.

https://doi.org/10.1136/jmg-2024-110163

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    Data availability statement

    Data are available upon reasonable request. Not applicable.

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    Footnotes

    • HH, XW and HZ contributed equally.

    • Collaborators Not applicable.

    • Contributors WZ and GL designed the study. WZ analysed the data and wrote the manuscript. HH, XW, HZ, JS and FM performed the research. SZ, YG, FG and HZ performed the clinical work. WZ acts as the guarantor.

    • Funding This work was supported by the National Key R&D Program of China (2023YFC2705504), the National Natural Science Foundation of China (82371672), the Natural Science Foundation of Hunan Province (2024JJ2083), the Science and Technology Innovation Program of Hunan Province (2023RC3233) and the Scientific Research Foundation of Reproductive and Genetic Hospital of CITIC-XIANGYA (YNXM-202202).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.