Homozygous CCDC146 mutation causes oligoasthenoteratozoospermia in humans and mice  

作　　者：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 

机构地区：[1]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 [2]Institute of Andrology,Nanjing Drum Tower Hospital,Affiliated Hospital of Nanjing University Medical School,Nanjing,Jiangsu 210008,China

出　　处：《Zoological Research》2024年第5期1073-1087,共15页动物学研究（英文）

基　　金：supported by the National Key Research and Developmental Program of China(2021YFC2700202,2022YFC2702601,2019YFA0802600,2022YFA0806303);National Natural Science Foundation of China(32470915,32000587,32270901,82171601);Global Select Project(DJK-LX-2022010)of the Institute of Health and Medicine,Hefei Comprehensive National Science Center,Joint Fund for New Medicine of USTC(YD9100002034);Scientific Research Foundation for Scholars of the First Affiliated Hospital of USTC(RC2023054)。

摘　　要：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(Ccdc146^(mut/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 Ccdc146^(mut/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.

关 键 词：OLIGOASTHENOTERATOZOOSPERMIA Human infertility Sperm flagellum CCDC146 Intraflagellar transport IFT20 

分 类 号：R698.2[医药卫生—泌尿科学] R-332[医药卫生—外科学]