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Mutations in TUBB8 cause a multiplicity of phenotypes in human oocytes and early embryos
  1. Ruizhi Feng1,2,
  2. Zheng Yan3,
  3. Bin Li3,
  4. Min Yu4,
  5. Qing Sang1,2,
  6. Guoling Tian5,
  7. Yao Xu1,2,
  8. Biaobang Chen1,2,
  9. Ronggui Qu1,2,
  10. Zhaogui Sun6,
  11. Xiaoxi Sun4,
  12. Li Jin1,
  13. Lin He2,7,
  14. Yanping Kuang3,8,
  15. Nicholas J Cowan5,
  16. Lei Wang1,2
  1. 1State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, The People's Republic of China
  2. 2Institutes of Biomedical Sciences, Fudan University, Shanghai, The People's Republic of China
  3. 3Reproductive Medicine Center, Shanghai Ninth hospital, Shanghai Jiao Tong University, Shanghai, The People's Republic of China
  4. 4Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, The People's Republic of China
  5. 5Department of Biochemistry and Molecular Pharmacology, New York Langone University Medical Center, New York, USA
  6. 6Shanghai Institute of Planned Parenthood Research, Shanghai, The People's Republic of China
  7. 7Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, The People's Republic of China
  8. 8Shanghai Key Laboratory of Reproductive Medicine, Shanghai, The People's Republic of China
  1. Correspondence to Dr Lei Wang, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200032, China; wangleiwanglei{at}fudan.edu.cn

Abstract

Background TUBB8 is a primate-specific β-tubulin isotype whose expression is confined to oocytes and the early embryo. We previously found that mutations in TUBB8 caused oocyte maturation arrest. The objective was to describe newly discovered mutations in TUBB8 and to characterise the accompanying spectrum of phenotypes and modes of inheritance.

Methods and results Patients with oocyte maturation arrest were sequenced with respect to TUBB8. We investigated the effects of identified mutations in vitro, in cultured cells and in mouse oocytes. Seven heterozygous missense and two homozygous mutations were identified. These mutations cause a range of folding defects in vitro, different degrees of microtubule disruption upon expression in cultured cells and interfere to varying extents in the proper assembly of the meiotic spindle in mouse oocytes. Several of the newly discovered TUBB8 mutations result in phenotypic variability. For example, oocytes harbouring any of three missense mutations (I210V, T238M and N348S) could extrude the first polar body. Moreover, they could be fertilised, although the ensuing embryos became developmentally arrested. Surprisingly, oocytes from patients harbouring homozygous TUBB8 mutations that in either case preclude the expression of a functional TUBB8 polypeptide nonetheless contained identifiable spindles.

Conclusions Our data substantially expand the range of dysfunctional oocyte phenotypes incurred by mutation in TUBB8, underscore the independent nature of human oocyte meiosis and differentiation, extend the class of genetic diseases known as the tubulinopathies and provide new criteria for the qualitative evaluation of meiosis II (MII) oocytes for in vitro fertilization (IVF).

  • TUBB8
  • mutations
  • oocyte maturation arrest
  • female infertility

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