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

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

doi:10.1016/j.scib.2020.08.026

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

Sci Bull (Beijing). 2020 Dec 30;65(24):2120-2129. doi: 10.1016/j.scib.2020.08.026. Epub 2020 Aug 20.

Authors

Yuying Jiao¹, Suixing Fan¹, Nazish Jabeen¹, Huan Zhang¹, Ranjha Khan¹, Ghulam Murtaza¹, Hanwei Jiang¹, Asim Ali¹, Yang Li¹, Jianqiang Bao¹, Beibei Zhang¹, Jianze Xu¹, Bo Xu¹, Hafiz Muhammad Jafar Hussain¹, Qumar Zaman¹, Ihsan Khan¹, Ihtisham Bukhari¹, Furhan Iqbal², Ayesha Yousaf¹, Sobia Dil¹, Manan Khan¹, Niaz Ahmad³, Hui Ma⁴, Xiaohua Jiang⁵, Yuanwei Zhang⁶, Qinghua Shi⁷

Affiliations

¹ 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.
² Institute of Pure and Applied Biology, Zoology Division, Bahauddin Zakariya University, Multan 60800, Pakistan.
³ Shahbaz Sharif District Hospital, Multan 60800, Pakistan.
⁴ 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. Electronic address: clsmh@ustc.edu.cn.
⁵ 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. Electronic address: biojxh@ustc.edu.cn.
⁶ 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. Electronic address: zyuanwei@ustc.edu.cn.
⁷ 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. Electronic address: qshi@ustc.edu.cn.

PMID: 36732965
DOI: 10.1016/j.scib.2020.08.026

Abstract

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.

Keywords: Human infertility; Meiotic DSB formation failure; Meiotic arrest; Oocyte maturation failure; Programmed meiotic DNA double-strand breaks; TOP6BLmutation.