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Rescue of male infertility through correcting a genetic mutation causing meiotic arrest in spermatogonial stem cells

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Asian Journal of Andrology 2021年第6期23卷 590-599页

作者： Ying-Hua Wang Meng Yan Xi Zhang Xin-Yu Liu Yi-Fu Ding Chong-Ping Lai Ming-Han Tong Jin-Song Li State Key Laboratory of Cell Biology Shanghai Key Laboratory of Molecular AndrologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai 200031China State Key Laboratory of Molecular Biology Shanghai Key Laboratory of Molecular AndrologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesShanghai 200031China School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China School of Life Science Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China

Azoospermia patients who carry a monogenetic mutation that causes meiotic arrest may have their biological child through genetic correction in spermatogonial stem cells(SSCs).However,such therapy for infertility has not been experimentally investigated *** this study,a mouse model with an X-linked testis-expressed 11(TEX11)mutation(Tex11PM/Y)identified in azoospermia patients exhibited meiotic arrest due to aberrant chromosome ***11PM/Y SSCs could be isolated and expanded in vitro normally,and the mutation was corrected by clustered regularly interspaced short palindromic repeats(CRISPR)–CRISPR-associated endonuclease 9(Cas9),leading to the generation of repaired SSC ***-genome sequencing demonstrated that the mutation rate in repaired SSCs is comparable with that of autonomous mutation in untreated Tex11PM/Y SSCs,and no predicted off-target sites are *** SSCs could restore spermatogenesis in infertile males and give rise to fertile offspring at a high *** summary,our study establishes a paradigm for the treatment of male azoospermia by combining in vitro expansion of SSCs and gene therapy.

关键词： azoospermia gene therapy male infertility meiotic arrest spermatogonial stem cells testis-expressed 11

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A new TEX11 mutation causes azoospermia and testicular meiotic arrest

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Asian Journal of Andrology 2021年第5期23卷 510-515页

作者： Xiao-Chen Yu Meng-Jing Li Fei-Fei Cai Si-Jie Yang Hong-Bin Liu Hao-Bo Zhang Center for Reproductive Medicine Cheeloo College of MedicineShandong UniversityJinan 250012China Key Laboratory of Reproductive Endocrinology of Ministry of Education Shandong UniversityJinan 250012China Shandong Key Laboratory of Reproductive Medicine Jinan 250012China Shandong Provincial Clinical Research Center for Reproductive Health Jinan 25CX312China National Research Center for Assisted Reproductive Technology and Reproductive Genetics Shandong UniversityJinan 250012China

There are many unknown genetic factors that lead to infertility in nonobstructive azoospermia ***,we performed whole-exome sequencing in blood samples obtained from 40 azoospermia patients with meiotic arrest and found a novel c.151_154del(p.D51fs)frame-shift mutation in exon 3 of the testis expressed 11(TEX11)gene in one *** sequencing analysis of the patient and 288 fertile men was performed to validate the *** analysis showed TEX11 expression in late-pachytene spermatocytes and in round spermatids in fertile human *** contrast,testes of the patient with TEX11 mutation underwent meiotic arrest and lacked TEX11 *** blotting of human embryonic kidney(HEK293)cells transfected with a vector for the p.D51fs TEX11 variant detected no TEX11 *** conclusion,we identified a novel frame-shift mutation in the TEX11 gene in an azoospermia patient,emphasizing that this gene should be included in genetic screening panels for the clinical evaluation of azoospermia patients.

关键词： male infertility meiotic arrest nonobstructive azoospermia testis expressed 11

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

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Science Bulletin 2020年第24期65卷 2120-2129,M0006页

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 First Affiliated Hospital of University of Science and Technology of China Hefei 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 Biology Zoology DivisionBahauddin Zakariya UniversityMultan 60800Pakistan Shahbaz Sharif District Hospital Multan 60800Pakistan

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.

关键词： Programmed meiotic DNA double-strand breaks TOP6BL mutation meiotic DSB formation failure Human infertility Oocyte maturation failure meiotic arrest

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颗粒细胞上的配体NPPC及其受体NPR2维持小鼠卵母细胞减数分裂的阻滞

颗粒细胞上的配体NPPC及其受体NPR2维持小鼠卵母细胞减数分裂的阻...

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“细胞活动生命活力”——中国细胞生物学学会全体会员代表大会暨第十二次学术大会

作者：张美佳夏国良农业生物技术国家重点实验室中国农业大学生物学院

哺乳动物卵母细胞减数分裂开始于胎儿期,然后长期停滞在减数分裂前期的双线期,直到青春期排卵激素(LH)峰的到来才启动减数分裂(卵母细胞成熟)和排卵。早在上世纪60年代生殖生物学家就推测卵泡内存在一种小分子的蛋白质(多肽)抑制了卵母... 详细信息

哺乳动物卵母细胞减数分裂开始于胎儿期,然后长期停滞在减数分裂前期的双线期,直到青春期排卵激素(LH)峰的到来才启动减数分裂(卵母细胞成熟)和排卵。早在上世纪60年代生殖生物学家就推测卵泡内存在一种小分子的蛋白质(多肽)抑制了卵母细胞的成熟。但是长期以来没有得到证实。我们利用原位杂交方法发现C-型钠肽Nppc基因表达在卵泡壁周围的颗粒细胞中,而其受体Nor2基因主要表达在卵丘细胞中。在体外,NPPC阻止卵母细胞自发成熟,并能增加卵母细胞中cGMP和cAMP水平。在体内,Npr2和Nppc自发突变小鼠大腔卵泡中的卵母细胞发生了减数分裂,提前恢复成熟。该结果证实NPPC与其受体NPR2结合,通过cGMP抑制PDE3A的活性维持卵母细胞中高水平的cAMP,来阻止卵母细胞减数分裂的恢复。这对于卵母细胞成熟与排卵的同步化以及雌性的正常受精非常关键。进一步研究表明卵母细胞旁分泌因子GDF9、BMP15、bFGF,以及雌激素可通过促进卵丘细胞NPR2的表达,参与卵母细胞减数分裂阻滞。

关键词： NPPC meiotic arrest Oocytes Mouse

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