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Mutations in TUBB8 and Human Oocyte Meiotic Arrest

Journal Article · · New England Journal of Medicine
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  1. Fudan Univ., Shanghai (China). State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, MOE Key Laboratory of Contemporary Anthropology, and Collaborative Innovation Center of Genetics and Development, School of Life Sciences
  2. Shanghai Jiao Tong Univ. (China). Reproductive Medicine Center, Shanghai Ninth Hospital
  3. Fudan Univ., Shanghai (China). Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital
  4. Shanghai, Reproductive Medicine Center, Shaanxi Maternal and Child Care Service Center, Shaanxi (China)
  5. New York University Langone Medical Center, NY (United States). Department of Biochemistry and Molecular Pharmacology
  6. Univ. of Chicago, IL (United States). Department of Molecular Genetics and Cell Biology
  7. Univ. of Chicago, IL (United States). Department of Molecular Genetics and Cell Biology
  8. Fudan Univ., Shanghai (China). Department of Otolaryngology, Eye and ENT Hospital
  9. Shanghai Institute of Planned Parenthood Research (China)
  10. Fudan Univ., Shanghai (China). Department of Integrative Medicine and Neurobiology, State Key Laboratory of Medical Neurobiology, and Shanghai Medical College
  11. University of Gothenburg (Sweden). Department of Physiology–Endocrinology, Institute of Neuroscience and Physiology
  12. Southeast University, Nanjing (China). Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences
  13. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division
  14. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division; Univ. of California, Berkeley, CA (United States). Molecular and Cell Biology Department and the Howard Hughes Medical Institute
  15. Fudan Univ., Shanghai (China). State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, MOE Key Laboratory of Contemporary Anthropology, and Collaborative Innovation Center of Genetics and Development, School of Life Sciences; Shanghai Jiao Tong Univ. (China). Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education
  16. Univ. of Chicago, IL (United States). Department of Molecular Genetics and Cell Biology; Iowa State Univ., Ames, IA (United States). Department of Genetics, Development and Cell Biology
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BACKGROUND: We present that 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: Lastly, TUBB8 mutations have dominant-negative effects that disrupt microtubule behavior and oocyte meiotic spindle assembly and maturation, causing female infertility.
Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1379043
Journal Information:
New England Journal of Medicine, Journal Name: New England Journal of Medicine Journal Issue: 3 Vol. 374; ISSN 0028-4793
Country of Publication:
United States
Language:
English

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Regulation of chromosome segregation in oocytes and the cellular basis for female meiotic errors journal December 2017
Acquisition of oocyte competence to develop as an embryo: integrated nuclear and cytoplasmic events journal February 2018
The identification of novel mutations in PLCZ1 responsible for human fertilization failure and a therapeutic intervention by artificial oocyte activation journal January 2020
Systematic humanization of the yeast cytoskeleton discerns functionally replaceable from divergent human genes posted_content December 2019
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TUBB 1 dysfunction in inherited thrombocytopenia causes genome instability journal November 2018
Novel mutations in WEE2 : Expanding the spectrum of mutations responsible for human fertilization failure journal February 2019
A pannexin 1 channelopathy causes human oocyte death journal March 2019
Mutations in TUBB8 cause a multiplicity of phenotypes in human oocytes and early embryos journal June 2016
Genetic diagnosis of subfertility: the impact of meiosis and maternal effects journal February 2019
Mutations in NLRP2 and NLRP5 cause female infertility characterised by early embryonic arrest journal March 2019
Eg5 orchestrates porcine oocyte maturational progression by maintaining meiotic organelle arrangement journal May 2018
The tubulin code at a glance journal March 2017
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes journal October 2019
PATL 2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice journal April 2018
Systematic Humanization of the Yeast Cytoskeleton Discerns Functionally Replaceable from Divergent Human Genes journal June 2020

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59 BASIC BIOLOGICAL SCIENCES
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