Division of Reproduction and Genetics, First Affiliated Hospital of University of Science and Technology of China, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, University of Science and Technology of China, Hefei, Anhui 230026, China.
Institute of Andrology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
Zool Res. 2024 Sep 18;45(5):1073-1087. doi: 10.24272/j.issn.2095-8137.2024.019.
Infertility represents a significant health concern, with sperm quantity and quality being crucial determinants of male fertility. Oligoasthenoteratozoospermia (OAT) is characterized by reduced sperm motility, lower sperm concentration, and morphological abnormalities in sperm heads and flagella. Although variants in several genes have been implicated in OAT, its genetic etiologies and pathogenetic mechanisms remain inadequately understood. In this study, we identified a homozygous nonsense mutation (c.916C>T, p.Arg306*) in the coiled-coil domain containing 146 ( ) gene in an infertile male patient with OAT. This mutation resulted in the production of a truncated CCDC146 protein (amino acids 1-305), retaining only two out of five coiled-coil domains. To validate the pathogenicity of the mutation, we generated a mouse model ( ) with a similar mutation to that of the patient. Consistently, the mice exhibited infertility, characterized by significantly reduced sperm counts, diminished motility, and multiple defects in sperm heads and flagella. Furthermore, the levels of axonemal proteins, including DNAH17, DNAH1, and SPAG6, were significantly reduced in the sperm of mice. Additionally, both human and mouse CCDC146 interacted with intraflagellar transport protein 20 (IFT20), but this interaction was lost in the mutated versions, leading to the degradation of IFT20. This study identified a novel deleterious homozygous nonsense mutation in that causes male infertility, potentially by disrupting axonemal protein transportation. These findings offer valuable insights for genetic counseling and understanding the mechanisms underlying mutant-associated infertility in human males.
不育症是一个重大的健康问题，精子数量和质量是男性生育能力的关键决定因素。少弱畸形精子症（OAT）的特征是精子活力降低、精子浓度降低以及精子头部和鞭毛的形态异常。尽管已经有几个基因的变异与 OAT 相关，但它的遗传病因和发病机制仍未得到充分理解。在这项研究中，我们在一名患有 OAT 的不育男性患者中发现了 coiled-coil 域包含 146 （CCDC146）基因的纯合无义突变（c.916C>T，p.Arg306*）。该突变导致产生了一个截断的 CCDC146 蛋白（氨基酸 1-305），仅保留了五个 coiled-coil 结构域中的两个。为了验证突变的致病性，我们构建了一个具有与患者相似突变的小鼠模型（ ）。一致地， 小鼠表现出不育，特征是精子数量显著减少、活力降低以及精子头部和鞭毛的多种缺陷。此外，axonemal 蛋白（包括 DNAH17、DNAH1 和 SPAG6）的水平在 小鼠的精子中显著降低。此外，人源和鼠源 CCDC146 均与内鞭毛运输蛋白 20（IFT20）相互作用，但在突变体中这种相互作用丢失，导致 IFT20 的降解。本研究在 CCDC146 中发现了一种新的有害纯合无义突变，可能通过破坏 axonemal 蛋白运输导致男性不育。这些发现为遗传咨询和理解人类男性中 CCDC146 突变相关不育的机制提供了有价值的见解。
