A TOP6BL mutation abolishes meiotic DNA double-strand break formation and causes human infertility

作     者：Yuying Jiao Suixing Fan Nazish Jabeen Huan Zhang Ranjha Khan Ghulam Murtaza Hanwei Jiang Asim Ali Yang Li Jianqiang Bao Beibei Zhang Jianze Xu Bo Xu Hafiz Muhammad Jafar Hussain Qumar Zaman Ihsan Khan Ihtisham Bukhari Furhan Iqbal Ayesha Yousaf Sobia Dil Manan Khan Niaz Ahmad Hui Ma Xiaohua Jiang Yuanwei Zhang Qinghua Shi 焦玉莹;樊岁兴;Nazish Jabeen;张欢;Ranjha Khan;Ghulam Murtaza;蒋涵玮;Asim Ali;李阳;鲍坚强;张贝贝;徐建泽;许波;Hafiz Muhammad Jafar Hussain;Qumar Zaman;Ihsan Khan;Ihtisham Bukhari;Furhan Iqbal;Ayesha Yousaf;Sobia Dil;Manan Khan;Niaz Ahmad;马慧;江小华;张远伟;史庆华

作者机构：First Affiliated Hospital of University of Science and Technology of ChinaHefei National Laboratory for Physical Sciences at Microscalethe CAS Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Sciences and MedicineCAS Center for Excellence in Molecular Cell ScienceCollaborative Innovation Center of Genetics and DevelopmentUniversity of Science and Technology of ChinaHefei 230027China Institute of Pure and Applied BiologyZoology DivisionBahauddin Zakariya UniversityMultan 60800Pakistan Shahbaz Sharif District HospitalMultan 60800Pakistan 

出 版 物：《Science Bulletin》 (科学通报（英文版）)

年 卷 期：2020年第65卷第24期

页      面：2120-2129,M0006页

核心收录：

学科分类：1002[医学-临床医学] 100211[医学-妇产科学] 10[医学] 

基　　金：supported by the National Key Research and Developmental Program of China (2018YFC1003700, 2016YFC1000600, 2018YFC1003400 and 2018YFC1004700) the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19000000) the National Natural Science Foundation of China (31890780, 31630050, 31871514 and 31771668) 

主　　题：Programmed meiotic DNA double-strand breaks TOP6BL mutation Meiotic DSB formation failure Human infertility Oocyte maturation failure Meiotic arrest 

摘      要：Meiosis is pivotal for sexual reproduction and fertility. Meiotic programmed DNA double-strand breaks(DSBs) initiate homologous recombination, ensuring faithful chromosome segregation and generation of gametes. However, few studies have focused on meiotic DSB formation in human ***, we report four infertile siblings born to a consanguineous marriage, with three brothers suffering from non-obstructive azoospermia and one sister suffering from unexplained infertility with normal menstrual cycles and normal ovary sizes with follicular activity. An autosomal recessive mutation in TOP6BL was found co-segregating with infertility in this family. Investigation of one male patient revealed failure in programmed meiotic DSB formation and meiotic arrest prior to pachytene stage of prophase *** models carrying similar mutations to that in patients recapitulated the spermatogenic abnormalities of the patient. Pathogenicity of the mutation in the female patient was supported by observations in mice that meiotic programmed DSBs failed to form in mutant oocytes and oocyte maturation failure due to absence of meiotic recombination. Our study thus illustrates the phenotypical characteristics and the genotype-phenotype correlations of meiotic DSB formation failure in humans.