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Mutations in TUBB8 and Human Oocyte Meiotic Arrest

  • Author(s): Feng, R
  • Sang, Q
  • Kuang, Y
  • Sun, X
  • Yan, Z
  • Zhang, S
  • Shi, J
  • Tian, G
  • Luchniak, A
  • Fukuda, Y
  • Li, B
  • Yu, M
  • Chen, J
  • Xu, Y
  • Guo, L
  • Qu, R
  • Wang, X
  • Sun, Z
  • Liu, M
  • Shi, H
  • Wang, H
  • Feng, Y
  • Shao, R
  • Chai, R
  • Li, Q
  • Xing, Q
  • Zhang, R
  • Nogales, E
  • Jin, L
  • He, L
  • Gupta, ML
  • Cowan, NJ
  • Wang, L
  • et al.

Published Web Location

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1510791
No data is associated with this publication.
Abstract

Copyright © 2016 Massachusetts Medical Society. All rights reserved. BACKGROUND: Human reproduction depends on the fusion of a mature oocyte with a sperm cell to form a fertilized egg. The genetic events that lead to the arrest of human oocyte maturation are unknown. METHODS: We sequenced the exomes of five members of a four-generation family, three of whom had infertility due to oocyte meiosis I arrest. We performed Sanger sequencing of a candidate gene, TUBB8, in DNA samples from these members, additional family members, and members of 23 other affected families. The expression of TUBB8 and all other β-tubulin isotypes was assessed in human oocytes, early embryos, sperm cells, and several somatic tissues by means of a quantitative reverse- transcriptase-polymerase-chain-reaction assay. We evaluated the effect of the TUBB8 mutations on the assembly of the heterodimer consisting of one α-tubulin polypeptide and one β-tubulin polypeptide (α/β-tubulin heterodimer) in vitro, on microtubule architecture in HeLa cells, on microtubule dynamics in yeast cells, and on spindle assembly in mouse and human oocytes. RESULTSL: We identified seven mutations in the primate-specific gene TUBB8 that were responsible for oocyte meiosis I arrest in 7 of the 24 families. TUBB8 expression is unique to oocytes and the early embryo, in which this gene accounts for almost all the expressed β-tubulin. The mutations affect chaperone-dependent folding and assembly of the α/β-tubulin heterodimer, disrupt microtubule behavior on expression in cultured cells, alter microtubule dynamics in vivo, and cause catastrophic spindle-assembly defects and maturation arrest on expression in mouse and human oocytes. CONCLUSIONS: TUBB8 mutations have dominant-negative effects that disrupt microtubule behavior and oocyte meiotic spindle assembly and maturation, causing female infertility.

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