Jing-Wei Ye, Tanveer Abbas, Jian-Teng Zhou, Jing Chen, Meng-Lei Yang, Xiong-Heng Huang, Huan Zhang, Hui Ma, Ao Ma, Bo Xu, Ghulam Murtaza, Qing-Hua Shi, Bao-Lu Shi
{"title":"Homozygous <i>CCDC146</i> mutation causes oligoasthenoteratozoospermia in humans and mice.","authors":"Jing-Wei Ye, Tanveer Abbas, Jian-Teng Zhou, Jing Chen, Meng-Lei Yang, Xiong-Heng Huang, Huan Zhang, Hui Ma, Ao Ma, Bo Xu, Ghulam Murtaza, Qing-Hua Shi, Bao-Lu Shi","doi":"10.24272/j.issn.2095-8137.2024.019","DOIUrl":null,"url":null,"abstract":"<p><p>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 ( <i>CCDC146</i>) 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 <i>CCDC146</i> mutation, we generated a mouse model ( <i>Ccdc146</i> <sup><i>mut/mut</i></sup> ) with a similar mutation to that of the patient. Consistently, the <i>Ccdc146</i> <sup><i>mut/mut</i></sup> 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 <i>Ccdc146</i> <sup><i>mut/mut</i></sup> 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 <i>CCDC146</i> that causes male infertility, potentially by disrupting axonemal protein transportation. These findings offer valuable insights for genetic counseling and understanding the mechanisms underlying <i>CCDC146</i> mutant-associated infertility in human males.</p>","PeriodicalId":48636,"journal":{"name":"Zoological Research","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11491774/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Zoological Research","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.24272/j.issn.2095-8137.2024.019","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ZOOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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 ( CCDC146) 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 CCDC146 mutation, we generated a mouse model ( Ccdc146mut/mut ) with a similar mutation to that of the patient. Consistently, the Ccdc146mut/mut 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 Ccdc146mut/mut 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 CCDC146 that causes male infertility, potentially by disrupting axonemal protein transportation. These findings offer valuable insights for genetic counseling and understanding the mechanisms underlying CCDC146 mutant-associated infertility in human males.
期刊介绍:
Established in 1980, Zoological Research (ZR) is a bimonthly publication produced by Kunming Institute of Zoology, the Chinese Academy of Sciences, and the China Zoological Society. It publishes peer-reviewed original research article/review/report/note/letter to the editor/editorial in English on Primates and Animal Models, Conservation and Utilization of Animal Resources, and Animal Diversity and Evolution.