Abstract
Purpose
TUBB8 is a gene that is frequently analysed in the genetic diagnosis of female infertility; 102 variants of this gene have been identified. However, the evaluation of its pathogenicity and the resulting phenotypes vary. Here, we aimed to identify novel TUBB8 variants as well as to summarize the reported variants and phenotypes in order for them to be included in genetic counselling analyses.
Methods
We performed whole exome sequencing to screen for candidate variants in 100 infertile female subjects and 100 controls who were able to conceive naturally. All variants were confirmed by Sanger sequencing. The effects of the variants in oocytes/arrested embryos were assessed by morphological observations, polar body biopsies, and chromosome analysis. A molecular modelling analysis was used to evaluate the possible effects of variants on protein secondary structure.
Results
We identified 29 TUBB8 variants, of which 20 were novel and five were maternally inherited. We identified three of a total of six recurrent variants that were specific for complete cleavage failure. Moreover, we obtained evidence that TUBB8 variants with large polar bodies had chromosome segregation errors.
Conclusions
Our study expands the spectrum of TUBB8 variants, particularly for embryonic arrest. Together with the extant knowledge of TUBB8 variants, this study provides a foundation for the genetic counselling of female infertility.
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Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
References
Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA. National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med. 2012;9(12):e1001356. https://doi.org/10.1371/journal.pmed.1001356.
Hart RJ. Physiological aspects of female fertility: role of the environment, modern lifestyle, and genetics. Physiol Rev. 2016;96(3):873–909. https://doi.org/10.1152/physrev.00023.2015.
Matzuk MM, Lamb DJ. The biology of infertility: research advances and clinical challenges. Nat Med. 2008;14(11):1197–213. https://doi.org/10.1038/nm.f.1895.
Yatsenko SA, Rajkovic A. Genetics of human female infertilitydagger. Biol Reprod. 2019;101(3):549–66. https://doi.org/10.1093/biolre/ioz084.
Moor RM, Dai Y, Lee C, Fulka J Jr. Oocyte maturation and embryonic failure. Hum Reprod Update. 1998;4(3):223–36. https://doi.org/10.1093/humupd/4.3.223.
Sha QQ, Zhang J, Fan HY. A story of birth and death: mRNA translation and clearance at the onset of maternal-to-zygotic transition in mammalsdagger. Biol Reprod. 2019;101(3):579–90. https://doi.org/10.1093/biolre/ioz012.
Feng R, Sang Q, Kuang Y, Sun X, Yan Z, Zhang S, et al. Mutations in TUBB8 and human oocyte meiotic arrest. New Engl J Med. 2016;374(3):223–32. https://doi.org/10.1056/NEJMoa1510791.
Feng R, Yan Z, Li B, Yu M, Sang Q, Tian G, et al. Mutations in TUBB8 cause a multiplicity of phenotypes in human oocytes and early embryos. J Med Genet. 2016;53(10):662–71. https://doi.org/10.1136/jmedgenet-2016-103891.
Chen B, Li B, Li D, Yan Z, Mao X, Xu Y, 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;32(2):457–64. https://doi.org/10.1093/humrep/dew322.
Huang L, Tong X, Luo L, Zheng S, Jin R, Fu Y, et al. Mutation analysis of the TUBB8 gene in nine infertile women with oocyte maturation arrest. Reprod Biomed Online. 2017;35(3):305–10. https://doi.org/10.1016/j.rbmo.2017.05.017.
Wang AC, Zhang YS, Wang BS, Zhao XY, Wu FX, Zhai XH, et al. Mutation analysis of the TUBB8 gene in primary infertile women with arrest in oocyte maturation. Gynecol Endocrinol. 2018;34(10):900–4. https://doi.org/10.1080/09513590.2018.1464138.
Yuan P, Zheng L, Liang H, Li Y, Zhao H, Li R, et al. A novel mutation in the TUBB8 gene is associated with complete cleavage failure in fertilized eggs. J Assist Reprod Genet. 2018;35(7):1349–56. https://doi.org/10.1007/s10815-018-1188-3.
Chen B, Wang W, Peng X, Jiang H, Zhang S, Li D, et al. The comprehensive mutational and phenotypic spectrum of TUBB8 in female infertility. European journal of human genetics: EJHG. 2019;27(2):300–7. https://doi.org/10.1038/s41431-018-0283-3.
Lanuza-Lopez MC, Martinez-Garza SG, Solorzano-Vazquez JF, Paz-Cervantes D, Gonzalez-Ortega C, Maldonado-Rosas I, et al. Oocyte maturation arrest produced by TUBB8 mutations: impact of genetic disorders in infertility treatment. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2020;36:1–6. https://doi.org/10.1080/09513590.2020.1725968.
Xing Q, Wang R, Chen B, Li L, Pan H, Li T, et al. Rare homozygous mutation in TUBB8 associated with oocyte maturation defect-2 in a consanguineous mating family. J Ovarian Res. 2020;13(1):42. https://doi.org/10.1186/s13048-020-00637-4.
Jia Y, Li K, Zheng C, Tang Y, Bai D, Yin J, et al. Identification and rescue of a novel TUBB8 mutation that causes the first mitotic division defects and infertility. J Assist Reprod Genet. 2020;37:2713–22. https://doi.org/10.1007/s10815-020-01945-w.
Sha Q, Zheng W, Feng X, Yuan R, Hu H, Gong F, et al. Novel mutations in TUBB8 expand the mutational and phenotypic spectrum of patients with zygotes containing multiple pronuclei. Gene. 2021;769:145227. https://doi.org/10.1016/j.gene.2020.145227.
Yang P, Yin C, Li M, Ma S, Cao Y, Zhang C, et al. Mutation analysis of tubulin beta 8 class VIII in infertile females with oocyte or embryonic defects. Clin Genet. 2021;99(1):208–14. https://doi.org/10.1111/cge.13855.
Zheng W, Zhou Z, Sha Q, Niu X, Sun X, Shi J, et al. Homozygous mutations in BTG4 cause zygotic cleavage failure and female infertility. Am J Hum Genet. 2020;107(1):24–33. https://doi.org/10.1016/j.ajhg.2020.05.010.
Xie P, Hu L, Tan Y, Gong F, Zhang S, Xiong B, et al. Retrospective analysis of meiotic segregation pattern and interchromosomal effects in blastocysts from inversion preimplantation genetic testing cycles. Fertil Steril. 2019;112(2):336–42 e3. https://doi.org/10.1016/j.fertnstert.2019.03.041.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24. https://doi.org/10.1038/gim.2015.30.
Zhao L, Guan Y, Wang W, Chen B, Xu S, Wu L, 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;37(8):1837–47. https://doi.org/10.1007/s10815-020-01830-6.
Choi T, Fukasawa K, Zhou R, Tessarollo L, Borror K, Resau J, et al. The Mos/mitogen-activated protein kinase (MAPK) pathway regulates the size and degradation of the first polar body in maturing mouse oocytes. Proc Natl Acad Sci U S A. 1996;93(14):7032–5. https://doi.org/10.1073/pnas.93.14.7032.
Xu Y, Shi Y, Fu J, Yu M, Feng R, Sang Q, et al. Mutations in PADI6 cause female infertility characterized by early embryonic arrest. Am J Hum Genet. 2016;99(3):744–52. https://doi.org/10.1016/j.ajhg.2016.06.024.
Chen B, Zhang Z, Sun X, Kuang Y, Mao X, Wang X, et al. Biallelic mutations in PATL2 cause female infertility characterized by oocyte maturation arrest. Am J Hum Genet. 2017;101(4):609–15. https://doi.org/10.1016/j.ajhg.2017.08.018.
Sang Q, Li B, Kuang Y, Wang X, Zhang Z, Chen B, et al. Homozygous mutations in WEE2 cause fertilization failure and female infertility. Am J Hum Genet. 2018;102(4):649–57. https://doi.org/10.1016/j.ajhg.2018.02.015.
Zheng W, Hu H, Dai J, Zhang S, Gu Y, Dai C, et al. Expanding the genetic and phenotypic spectrum of the subcortical maternal complex genes in recurrent preimplantation embryonic arrest. Clin Genet. 2021;99(2):286–91. https://doi.org/10.1111/cge.13858.
Acknowledgements
We would like to thank the patients and their families for participating in this work and Editage (www.editage.cn) for English language editing.
Funding
This work was supported by the National Natural Science Foundation of China (grant number 82001633), China Postdoctoral Science Foundation (grant number 2020M682575), the Changsha Municipal Natural Science Foundation (grant number kq2007022), the Research Grant of CITIC-XIANGYA (grant number YNXM-201913), and the Hunan Provincial Grant for Innovative Province Construction (2019SK4012).
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W.Z. and G.L. performed study design. W.Z. performed study execution and statistical analysis and wrote the manuscript. H.H., X.X., and Y.G performed the variant arrangement. S.Z., F.G., and G.L. performed the patient recruitment.
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Zheng, W., Hu, H., Zhang, S. et al. The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility. J Assist Reprod Genet 38, 2261–2272 (2021). https://doi.org/10.1007/s10815-021-02219-9
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DOI: https://doi.org/10.1007/s10815-021-02219-9