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., ... Wang, L. (2016). Mutations in TUBB8 and Human Oocyte Meiotic Arrest. New England Journal of Medicine, 374(3), 223-232. https://doi.org/10.1056/NEJMoa1510791
@article{3702923449c84a3ea0a09b5ffa378368,
title = "Mutations in TUBB8 and Human Oocyte Meiotic Arrest",
abstract = "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.",
author = "Ruizhi Feng and Qing Sang and Yanping Kuang and Xiaoxi Sun and Zheng Yan and Shaozhen Zhang and Juanzi Shi and Guoling Tian and Anna Luchniak and Yusuke Fukuda and Bin Li and Min Yu and Junling Chen and Yao Xu and Luo Guo and Ronggui Qu and Xueqian Wang and Zhaogui Sun and Miao Liu and Huijuan Shi and Hongyan Wang and Yi Feng and Ruijin Shao and Renjie Chai and Qiaoli Li and Qinghe Xing and Rui Zhang and Eva Nogales and Li Jin and Lin He and Gupta, {Mohan L.} and Cowan, {Nicholas J.} and Lei Wang",
note = "Publisher Copyright: Copyright {\textcopyright} 2016 Massachusetts Medical Society. All rights reserved.",
year = "2016",
month = jan,
day = "21",
doi = "10.1056/NEJMoa1510791",
language = "English",
volume = "374",
pages = "223--232",
journal = "New England Journal of Medicine",
issn = "0028-4793",
publisher = "Massachussetts Medical Society",
number = "3",
}
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 2016, 'Mutations in TUBB8 and Human Oocyte Meiotic Arrest', New England Journal of Medicine, vol. 374, no. 3, pp. 223-232. https://doi.org/10.1056/NEJMoa1510791
TY - JOUR
T1 - Mutations in TUBB8 and Human Oocyte Meiotic Arrest
AU - Feng, Ruizhi
AU - Sang, Qing
AU - Kuang, Yanping
AU - Sun, Xiaoxi
AU - Yan, Zheng
AU - Zhang, Shaozhen
AU - Shi, Juanzi
AU - Tian, Guoling
AU - Luchniak, Anna
AU - Fukuda, Yusuke
AU - Li, Bin
AU - Yu, Min
AU - Chen, Junling
AU - Xu, Yao
AU - Guo, Luo
AU - Qu, Ronggui
AU - Wang, Xueqian
AU - Sun, Zhaogui
AU - Liu, Miao
AU - Shi, Huijuan
AU - Wang, Hongyan
AU - Feng, Yi
AU - Shao, Ruijin
AU - Chai, Renjie
AU - Li, Qiaoli
AU - Xing, Qinghe
AU - Zhang, Rui
AU - Nogales, Eva
AU - Jin, Li
AU - He, Lin
AU - Gupta, Mohan L.
AU - Cowan, Nicholas J.
AU - Wang, Lei
N1 - Publisher Copyright:
Copyright © 2016 Massachusetts Medical Society. All rights reserved.
PY - 2016/1/21
Y1 - 2016/1/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84996553590&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa1510791
DO - 10.1056/NEJMoa1510791
M3 - Review article
C2 - 26789871
AN - SCOPUS:84996553590
SN - 0028-4793
VL - 374
SP - 223
EP - 232
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 3
ER -