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A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family

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Asian Journal of Andrology 2023年第3期25卷 350-355页

作者： sobia dil Asad Khan Ahsanullah Unar Meng-Lei Yang Imtiaz Ali Aurang Zeb Huan Zhang Jian-Teng Zhou Muhammad Zubair Khalid Khan Shun Bai Qing-Hua Shi Division of Reproduction and Genetics The First Affiliated Hospital of University of Science and Technology of ChinaSchool of Basic Medical SciencesDivision of Life Sciences and MedicineBiomedical Sciences and Health Laboratory of Anhui ProvinceUniversity of Science and Technology of ChinaHefei 230027China

Multiple morphological abnormalities of the sperm flagella(MMAF)is a severe form of asthenozoospermia categorized by immotile spermatozoa with abnormal flagella in ejaculate.Whole-exome sequencing(WES)is used to detect pathogenic variants in patients with MMAF.In this study,a novel homozygous frameshift variant(c.6158_6159insT)in dynein axonemal heavy chain 8(DNAH8)from two infertile brothers with MMAF in a consanguineous Pakistani family was identified by WES.Reverse transcription-polymerase chain reaction(RT-PCR)confirmed DNAH8 mRNA decay in these patients with the DNAH8 mutation.Hematoxylin–eosin staining and transmission electron microscopy revealed highly divergent morphology and ultrastructure of sperm flagella in these patients.Furthermore,an immunofluorescence assay showed the absence of DNAH8 and a reduction in its associated protein DNAH17 in the patients'spermatozoa.Collectively,our study expands the phenotypic spectrum of patients with DNAH8-related MMAF worldwide.

关键词： DNAH8 gene mutation male infertility multiple morphological abnormalities of the sperm flagella

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Novel biallelic loss-of-function mutations in CFAP43 cause multiple morphological abnormalities of the sperm flagellum in Pakistani families

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Asian Journal of Andrology 2021年第6期23卷 627-632页

作者： Ihsan Khan Basit Shah sobia dil Nadeem Ullah Jian-Teng Zhou Da-Ren Zhao Yuan-Wei Zhang Xiao-Hua Jiang Ranjha Khan Asad Khan Haider Ali Muhammad Zubair Wasim Shah Huan Zhang Qing-Hua Shi First Affiliated Hospital of USTC 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

Multiple morphological abnormalities of the sperm flagella(MMAF)is a specific type of asthenoteratozoospermia,presenting with multiple morphological anomalies in spermatozoa,such as absent,bent,coiled,short,or irregular caliber flagella.Previous genetic studies revealed pathogenic mutations in genes encoding cilia and flagella-associated proteins(CFAPs;e.g.,CFAP43,CFAP44,CFAP65,CFAP69,CFAP70,and CFAP251)responsible for the MMAF phenotype in infertile men from different ethnic groups.However,none of them have been identified in infertile Pakistani males with MMAF.In the current study,two Pakistani families with MMAF patients were recruited.Whole-exome sequencing(WES)of patients and their parents was performed.WES analysis reflected novel biallelic loss-of-function mutations in CFAP43 in both families(Family 1:ENST00000357060.3,p.Arg300Lysfs*22 and p.Thr526Serfs*43 in a compound heterozygous state;Family 2:ENST00000357060.3,p.Thr526Serfs*43 in a homozygous state).Sanger sequencing further confirmed that these mutations were segregated recessively in the families with the MMAF phenotype.Semiquantitative reverse-transcriptase polymerase chain reaction(qRT-PCR)was carried out to detect the effect of the mutation on mRNA of the affected gene.Previous research demonstrated that biallelic loss-of-function mutations in CFAP43 accounted for the majority of all CFAP43-mutant MMAF patients.To the best of our knowledge,this is the first study to report CFAP43 biallelic loss-of-function mutations in a Pakistani population with the MMAF phenotype.This study will help researchers and clinicians to understand the genetic etiology of MMAF better.

关键词： cilia and flagella-associated proteins male infertility multiple morphological abnormalities of the sperm flagella whole-exome sequencing

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TOL6BL突变导致减数分裂程序性DNA双链断裂无法产生和人类不孕

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

作者：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 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

我们找到一个近亲婚配后代不育家系,该家系有3位非梗阻性无精子症患者和1位原因不明的女性不孕患者.全外显子组测序结合Sanger测序分析发现TOP6BL的c.483dup T突变在该家系中与不孕呈隐性共分离.正常的TOP6BL可与SPO11β结合进而导致减... 详细信息

我们找到一个近亲婚配后代不育家系,该家系有3位非梗阻性无精子症患者和1位原因不明的女性不孕患者.全外显子组测序结合Sanger测序分析发现TOP6BL的c.483dup T突变在该家系中与不孕呈隐性共分离.正常的TOP6BL可与SPO11β结合进而导致减数分裂程序性DNA双链断裂(DSBs)产生,而该突变破坏了二者的结合.对家系中一位男患者的精母细胞进行分析,发现其同源染色体联会异常,减数分裂不能到达粗线期,且染色体轴上缺少减数分裂重组蛋白RPA和DMC1信号,表明其减数分裂程序性DSBs未能产生.我们制备了携带类似患者突变的小鼠,发现突变雄鼠具有与男患者相同的减数分裂异常,突变雌鼠不孕,其卵母细胞中程序性DSBs和减数分裂重组也不能发生,卵母细胞不能成熟.这些发现表明TOP6BL突变可导致人类不孕,为相关不孕不育患者的病因诊断和人工辅助生殖胚胎的遗传检查提供了分子标靶.

关键词：全外显子组测序非梗阻性无精子症病因诊断近亲婚配染色体联会 DNA双链断裂减数分裂异常精母细胞

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