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N Engl J Med. 2016 Jan 21;374(3):223-32. doi: 10.1056/NEJMoa1510791.

Mutations in TUBB8 and Human Oocyte Meiotic Arrest.

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From the 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, Fudan University (R.F., Q.S., Y.X., R.Q., X.W., H.W., Q.L., Q.X., L.J., L.H., L.W.), Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University (X.S., M.Y., J.C.), Department of Otolaryngology, Eye and ENT Hospital, Fudan University (L.G.), Department of Integrative Medicine and Neurobiology, State Key Laboratory of Medical Neurobiology, and Shanghai Medical College, Fudan University (Y.F.), the Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University (Y.K., Z.Y., S.Z., B.L.), Shanghai Institute of Planned Parenthood Research (Z.S., M.L., H.S.), and Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University (L.H.), Shanghai, Reproductive Medicine Center, Shaanxi Maternal and Child Care Service Center, Shaanxi (J.S.), and Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing (R.C.) - all in China; the Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York (G.T., N.J.C.); the Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago (A.L., Y. Fukuda, M.L.G.); the Department of Physiology-Endocrinology, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden (R.S.); the Department of Genetics, Development and Cell Biology, Iowa State University, Ames (M.L.G.); and the Life Sciences Division, Lawrence Berkeley National Laboratory (R.Z., E.N.), the Molecular and Cell Biology Department (E.N.), and the Howard Hughes Medical Institute (E.N.), University of California Berkeley, Berkeley.


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. Results 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. (Funded by the National Basic Research Program of China and others.).

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