Jiao Yuying, Fan Suixing, Jabeen Nazish, Zhang Huan, Khan Ranjha, Murtaza Ghulam, Jiang Hanwei, Ali Asim, Li Yang, Bao Jianqiang, Zhang Beibei, Xu Jianze, Xu Bo, Hussain Hafiz Muhammad Jafar, Zaman Qumar, Khan Ihsan, Bukhari Ihtisham, Iqbal Furhan, Yousaf Ayesha, Dil Sobia, Khan Manan, Ahmad Niaz, Ma Hui, Jiang Xiaohua, Zhang Yuanwei, Shi Qinghua
First Affiliated Hospital of University of Science and Technology of China, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center of Genetics and Development, University of Science and Technology of China, Hefei 230027, China.
Institute of Pure and Applied Biology, Zoology Division, Bahauddin Zakariya University, Multan 60800, Pakistan.
Sci Bull (Beijing). 2020 Dec 30;65(24):2120-2129. doi: 10.1016/j.scib.2020.08.026. Epub 2020 Aug 20.
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 reproduction. Here, 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 I. Mouse 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.
减数分裂对于有性生殖和生育能力至关重要。减数分裂程序性DNA双链断裂（DSB）启动同源重组，确保染色体忠实分离并产生配子。然而，很少有研究关注人类生殖中减数分裂DSB的形成。在此，我们报告了一对近亲结婚所生的四个不育兄弟姐妹，其中三个兄弟患有非梗阻性无精子症，一个姐妹患有不明原因的不孕症，其月经周期正常，卵巢大小正常且有卵泡活动。在这个家族中发现TOP6BL基因的常染色体隐性突变与不孕症共分离。对一名男性患者的调查显示，减数分裂程序性DSB形成失败且在减数分裂前期I的粗线期之前减数分裂停滞。携带与患者相似突变的小鼠模型重现了患者的生精异常。雌性患者突变的致病性得到了小鼠实验结果的支持，即突变卵母细胞中减数分裂程序性DSB未能形成，并且由于缺乏减数分裂重组导致卵母细胞成熟失败。因此，我们的研究阐明了人类减数分裂DSB形成失败的表型特征以及基因型与表型的相关性。
