Loss of Different Domains of TDRD12 Leads to Distinct Male Infertility-Related Phenotypes.

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
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
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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.

TDRD12不同结构域的缺失导致不同的男性不育相关表型。
已知Tdrd12在小鼠精子发生中起重要作用。然而,将TDRD12突变与男性无精子症联系起来的证据有限,并且没有TDRD12相关的畸形精子症的病例报道。我们分别在两个无亲缘关系的不育男性中发现了两个新的纯合TDRD12突变(c.3378dupG和c.2463C>G)。患者1携带TDRD12移码突变(c.3378dupG),导致缺少富含半胱氨酸结构域的截断蛋白。该患者表现为畸形精子症,其特征是精子形态异常,包括头部和鞭毛缺陷。患者2携带TDRD12无义突变(c.2463C>G),导致该蛋白完全降解。该患者表现为无精子症,其特征是生殖细胞成熟在精母细胞阶段停止。机制上,预测关键的piRNA生物发生蛋白TDRKH、TDRD9、PIWIL2和PIWIL1与TDRD12相互作用。值得注意的是,患者1精子中PIWIL1荧光减少,而患者2睾丸组织中PIWIL2和TDRD9信号减弱,LINE-1信号增加。此外,使用患者1的精子进行胞浆内单精子注射失败。我们的研究首先确定了TDRD12不同结构域的缺失会导致不同的男性不育相关表型。这些发现揭示了男性不育症的新的遗传学见解,证明了TDRD12在人类精子发生中的关键作用,并有助于诊断和遗传咨询。
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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
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
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