Mutations in TUBB8 and Human Oocyte Meiotic Arrest

Ruizhi Feng, Qing Sang, Yanping Kuang, Xiaoxi Sun, Zheng Yan, Shaozhen Zhang, Juanzi Shi, Guoling Tian, Anna Luchniak, Yusuke Fukuda, Bin Li, Min Yu, Junling Chen, Yao Xu, Luo Guo, Ronggui Qu, Xueqian Wang, Zhaogui Sun, Miao Liu, Huijuan ShiHongyan Wang, Yi Feng, Ruijin Shao, Renjie Chai, Qiaoli Li, Qinghe Xing, Rui Zhang, Eva Nogales, Li Jin, Lin He, Mohan L. Gupta, Nicholas J. Cowan, Lei Wang

Research output: Contribution to journalReview articlepeer-review

122 Scopus citations


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.

Original languageEnglish
Pages (from-to)223-232
Number of pages10
JournalNew England Journal of Medicine
Issue number3
StatePublished - Jan 21 2016


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