The identification of genetic factors contributing to human oocytes maturation arrest using whole-genome sequencing

Мұқаба

Дәйексөз келтіру

Толық мәтін

Ашық рұқсат Ашық рұқсат
Рұқсат жабық Рұқсат берілді
Рұқсат жабық Тек жазылушылар үшін

Аннотация

Female fertility is dependent on the successful maturation of oocytes, a complex and meticulously regulated cellular process that prepares oocytes for fertilization and subsequent embryonic development. However, with advancing age and the onset of reproductive senescence, the probability of errors in this process increases significantly. These age-related alterations are associated with the accumulation of genetic and epigenetic abnormalities, mitochondrial dysfunction, and modifications in cytoskeletal function, all of which elevate the risk of oocyte maturation defects, embryonic developmental anomalies, and infertility. In this study, we conducted a genetic analysis of a patient experiencing female infertility due to oocyte maturation arrest and identified a heterozygous variant, c.527C>T (p.Ser176Leu), in the TUBB8 gene. This variant disrupts microtubule formation, leading to defects in meiotic spindle formation and subsequent oocyte arrest. Variants in the TUBB8 gene, which encodes a crucial component of microtubules, have been implicated in the pathogenesis of oocyte maturation arrest, abnormal fertilization, and other related disorders. Such changes may be particularly pronounced in women exhibiting characteristics of reproductive senescence.

Толық мәтін

Рұқсат жабық

Авторлар туралы

N. Arakelyan

Sirius University of Science and Technology

Email: manakhov@rogaevlab.ru

Center for Genetics and Life Science

Ресей, Sirius, 354340

A. Grigorenko

Vavilov Institute of General Genetics, Russian Academy of Sciences

Email: manakhov@rogaevlab.ru
Ресей, Moscow, 119991

V. Petrova

Sirius University of Science and Technology

Email: manakhov@rogaevlab.ru

Center for Genetics and Life Science

Ресей, Sirius, 354340

E. Vasilevskaya

Sirius University of Science and Technology

Email: manakhov@rogaevlab.ru

Center for Genetics and Life Science

Ресей, Sirius, 354340

D. Islamgulov

Fomin Clinic

Email: manakhov@rogaevlab.ru
Ресей, Ufa, 450078

A. Dolgikh

Fomin Clinic

Email: manakhov@rogaevlab.ru
Ресей, Ufa, 450078

A. Manakhov

Sirius University of Science and Technology; Vavilov Institute of General Genetics, Russian Academy of Sciences

Хат алмасуға жауапты Автор.
Email: manakhov@rogaevlab.ru

Center for Genetics and Life Science

Ресей, Sirius, 354340; Moscow, 119991

Әдебиет тізімі

  1. Feng R., Sang Q., Kuang Y. et al. Mutations in TUBB8 and human oocyte meiotic arrest // N. Engl. J. Med. 2016. V. 374. № 3. P. 223–232. https://doi.org/10.1056/NEJMoa1510791
  2. Lin T. Liu, W., Han W. et al. Genetic screening and analysis of TUBB8 variants in females seeking ART // Reproductive Biomedicine Online. 2023. V. 46. № 2. P. 244–254.
  3. Chen B., Wang W., Peng X. et al. The comprehensive mutational and phenotypic spectrum of TUBB8 in female infertility // Eur. J. Hum. Genet. 2019. V. 27. № 2. P. 300–307. https://doi.org/10.1038/s41431-018-0283-3
  4. Li H., Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform // Bioinformatics. 2009. V. 25. № 14. P. 1754–1760. https://doi.org/10.1093/bioinformatics/btp324
  5. McKenna A., Hanna M., Banks E. et al. The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data // Genome Research. 2010. V. 20. № 9. P. 1297–1303.
  6. Janke C. The tubulin code: Molecular components, readout mechanisms, and functions // J. Cell Biol. 2014. V. 206. № 4. P. 461–472. https://doi.org/10.1083/jcb.201406055
  7. Cao T., Guo J., Xu Y. et al. Two mutations in TUBB8 cause developmental arrest in human oocytes and early embryos // Reprod. Biomed. Online. 2021. V. 43. № 5. P. 891–898. https://doi.org/10.1016/j.rbmo.2021.07.020
  8. Chen B., Li B., Li D. et al. Novel mutations and structural deletions in TUBB8: Expanding mutational and phenotypic spectrum of patients with arrest in oocyte maturation, fertilization or early embryonic development // Hum. Reprod. 2017. V. 32. № 2. P. 457–464. https://doi.org/10.1093/humrep/dew322
  9. Chen T., Bian Y., Liu X. et al. A recurrent missense mutation in ZP3 causes empty follicle syndrome and female infertility // Am. J. Hum. Genet. 2017. V. 101. P. 459–465. https://doi.org/10.1016/j.ajhg.2017.08.001
  10. Dai C., Hu L., Gong F. et al. ZP2 pathogenic variants cause in vitro fertilization failure and female infertility // Genet. Med. 2019. V. 21. P. 431–440. https://doi.org/10.1038/s41436-018-0064-y
  11. Huang L., Tong X., Luo L. et al. Mutation analysis of the TUBB8 gene in nine infertile women with oocyte maturation arrest // Reprod. Biomed. Online. 2017. V. 35. P. 305–310. https://doi.org/10.1016/j.rbmo.2017.05.017
  12. Maddirevula S., Coskun S., Alhassan S. et al. Female infertility caused by mutations in the oocyte-specific translational repressor PATL2 // Am. J. Hum. Genet. 2017. V. 101. № 4. P. 603–608. https://doi.org/10.1016/j.ajhg.2017.08.009
  13. Sang Q., Li B., Kuang Y. et al. Homozygous mutations in WEE2 cause fertilization failure and female infertility // Am. J. Hum. Genet. 2018. V. 102. P. 649–657. https://doi.org/10.1016/j.ajhg.2018.02.015
  14. Wang A.C., Zhang Y.S., Wang B.S. et al. Mutation analysis of the TUBB8 gene in primary infertile women with arrest in oocyte maturation // Gynecol. Endocrinol. 2018. V. 34. № 10. P. 900–904. https://doi.org/10.1080/09513590.2018.1464138
  15. Xing Q., Wang R., Chen B. et al. Rare homozygous mutation in TUBB8 associated with oocyte maturation defect-2 in a consanguineous mating family // J. Ovarian Res. 2020. V. 13. № 1. P. 42. https://doi.org/10.1186/s13048-020-00637-4
  16. Yang P., Yin C., Li M. et al. Mutation analysis of tubulin beta 8 class VIII in infertile females with oocyte or embryonic defects // Clin. Genet. 2021. V. 99. № 1. P. 208–214. https://doi.org/10.1111/cge.13855
  17. Zhang Z., Li B., Fu J. et al. Bi-allelic missense pathogenic variants in TIRP13 cause female infertility characterized by oocyte maturation arrest // Am. J. Hum. Genet. 2020. V. 107. № 1. P. 15–23. https://doi.org/10.1016/j.ajhg.2020.05.001
  18. Zhao L., Guan Y., Wang W. et al. Identification novel mutations in TUBB8 in female infertility and a novel phenotype of large polar body in oocytes with TUBB8 mutations // J. Assist. Reprod. Genet. 2020. V. 37. № 8. P. 1837–1847. https://doi.org/10.1007/s10815-020-01830-6
  19. Zhao L., Xue S., Yao Z. et al. Biallelic mutations in CDC20 cause female infertility characterized by abnormalities in oocyte maturation and early embryonic development // Protein Cell. 2020. V. 11. P. 921–927. doi: 10.1007/s13238-020-00756-0
  20. McLaren W., Gil L., Hunt S.E. et al. The ensembl variant effect predictor // Genome Biol. 2016. V. 17. P. 122. https://doi.org/10.1186/s13059-016-0974-4
  21. Karczewski K.J., Francioli L.C., Tiao G. et al. The mutational constraint spectrum quantified from variation in 141,456 humans // Nature. 2020. V. 581. № 7809. P. 434–443. https://doi.org/10.1038/s41586-020-2308-7
  22. Vaser R., Adusumalli S., Leng S.N. et al. SIFT missense predictions for genomes // Nat. Protoc. 2016. V. 11. № 1. P. 1–9. https://doi.org/10.1038/nprot.2015.123
  23. Adzhubei I.A., Schmidt S., Peshkin L. et al. A method and server for predicting damaging missense mutations // Nat. Methods. 2010. V. 7. № 4. P. 248–249. https://doi.org/ 10.1038/nmeth0410-248

Қосымша файлдар

Қосымша файлдар
Әрекет
1. JATS XML
2. Fig. 1. Results of Sanger sequencing of the proband and her family members (TUBB8 c.527C>T, p.Ser176Leu).

Жүктеу (225KB)

© Russian Academy of Sciences, 2025