{"title":"Loss of Different Domains of TDRD12 Leads to Distinct Male Infertility-Related Phenotypes.","authors":"Xinyao Tang, Jinhui Li, Yunchuan Tian, Chanjuan Zhao, Xiaohui Jiang, Chuan Jiang, Xiang Wang, Jun Ma, Yingteng Zhang, Tiechao Ruan, Guicheng Zhao, Yihong Yang, Ying Shen","doi":"10.1111/cge.70034","DOIUrl":null,"url":null,"abstract":"<p><p>Tdrd12 is known to play an important role in spermatogenesis in mice. However, evidence linking TDRD12 mutations to male azoospermia is limited, and no cases of TDRD12-related teratozoospermia have been reported. We identified two novel homozygous TDRD12 mutations (c.3378dupG and c.2463C>G) in two unrelated infertile men, respectively. Patient 1 carried a TDRD12 frameshift mutation (c.3378dupG), resulting in a truncated protein lacking the cysteine-rich domain. This patient presented with teratozoospermia, characterized by abnormal sperm morphology, including defects in the head and flagellum. Patient 2 carried a TDRD12 nonsense mutation (c.2463C>G), resulting in complete degradation of the protein. This patient exhibited azoospermia, characterized by germ cell maturation arrest at the spermatocyte stage. Mechanistically, TDRKH, TDRD9, PIWIL2, and PIWIL1, key piRNA biogenesis proteins, are predicted to interact with TDRD12. Notably, PIWIL1 fluorescence was reduced in Patient 1's sperm, while PIWIL2 and TDRD9 signals were diminished and LINE-1 signal was increased in Patient 2's testicular tissue. Furthermore, Intracytoplasmic sperm injection using Patient 1's sperm was unsuccessful. Our study first identified that the loss of different domains of TDRD12 results in distinct male infertility-related phenotypes. These findings revealed novel genetic insights into male infertility, demonstrated the critical role of TDRD12 in human spermatogenesis, and are helpful for diagnosis and genetic counseling.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3000,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/cge.70034","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
Tdrd12 is known to play an important role in spermatogenesis in mice. However, evidence linking TDRD12 mutations to male azoospermia is limited, and no cases of TDRD12-related teratozoospermia have been reported. We identified two novel homozygous TDRD12 mutations (c.3378dupG and c.2463C>G) in two unrelated infertile men, respectively. Patient 1 carried a TDRD12 frameshift mutation (c.3378dupG), resulting in a truncated protein lacking the cysteine-rich domain. This patient presented with teratozoospermia, characterized by abnormal sperm morphology, including defects in the head and flagellum. Patient 2 carried a TDRD12 nonsense mutation (c.2463C>G), resulting in complete degradation of the protein. This patient exhibited azoospermia, characterized by germ cell maturation arrest at the spermatocyte stage. Mechanistically, TDRKH, TDRD9, PIWIL2, and PIWIL1, key piRNA biogenesis proteins, are predicted to interact with TDRD12. Notably, PIWIL1 fluorescence was reduced in Patient 1's sperm, while PIWIL2 and TDRD9 signals were diminished and LINE-1 signal was increased in Patient 2's testicular tissue. Furthermore, Intracytoplasmic sperm injection using Patient 1's sperm was unsuccessful. Our study first identified that the loss of different domains of TDRD12 results in distinct male infertility-related phenotypes. These findings revealed novel genetic insights into male infertility, demonstrated the critical role of TDRD12 in human spermatogenesis, and are helpful for diagnosis and genetic counseling.
期刊介绍:
Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice.
Topics of particular interest are:
• Linking genetic variations to disease
• Genome rearrangements and disease
• Epigenetics and disease
• The translation of genotype to phenotype
• Genetics of complex disease
• Management/intervention of genetic diseases
• Novel therapies for genetic diseases
• Developmental biology, as it relates to clinical genetics
• Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease