Mutations in TUBB8 and Human Oocyte Meiotic Arrest
| Autor: | Ronggui Qu, Eva Nogales, Qing Sang, Hongyan Wang, Huijuan Shi, Yi Feng, Zhaogui Sun, Qiaoli Li, Juanzi Shi, Min Yu, Rui Zhang, Qinghe Xing, Yanping Kuang, Xueqian Wang, Nicholas J. Cowan, Yusuke Fukuda, Ruijin Shao, Mohan L. Gupta, Shaozhen Zhang, Yao Xu, Li Jin, Lin He, Bin Li, Ruizhi Feng, Zheng Yan, Miao Liu, Anna Luchniak, Lei Wang, Renjie Chai, Luo Guo, Junling Chen, Guoling Tian, Xiaoxi Sun |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Adult Candidate gene Somatic cell 1.1 Normal biological development and functioning Reproductive health and childbirth Spindle Apparatus Biology medicine.disease_cause Medical and Health Sciences Microtubules 03 medical and health sciences Mice 0302 clinical medicine Underpinning research Microtubule Tubulin General & Internal Medicine Genetics medicine 2.1 Biological and endogenous factors Animals Humans Aetiology Gene Mutation 030219 obstetrics & reproductive medicine Contraception/Reproduction Embryo General Medicine Oocyte Sperm Molecular biology Cell biology Meiosis 030104 developmental biology medicine.anatomical_structure Infertility Oocytes RNA Female Generic health relevance Infertility Female |
| Zdroj: | The New England journal of medicine, vol 374, iss 3 Feng, R; Sang, Q; Kuang, Y; Sun, X; Yan, Z; Zhang, S; et al.(2016). Mutations in TUBB8 and Human Oocyte Meiotic Arrest. New England Journal of Medicine, 374(3), 223-232. doi: 10.1056/NEJMoa1510791. UC Berkeley: Retrieved from: http://www.escholarship.org/uc/item/9pg7g1nv |
| ISSN: | 1533-4406 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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