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 ...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.展开更多
Cilium,an organelle with a unique proteome and organization,protruding from the cell surface,generally serves as a force generator and signaling compartment.During ciliogenesis,ciliary proteins are synthesized in cyto...Cilium,an organelle with a unique proteome and organization,protruding from the cell surface,generally serves as a force generator and signaling compartment.During ciliogenesis,ciliary proteins are synthesized in cytoplasm and transported into cilia by intraflagellar transport(IFT)particles,where the inner counterparts undergo reverse trafficking.The homeostasis of IFT plays a key role in cilial structure assembly and signaling transduction.Much progress has been made on the mechanisms and functions of IFT;however,recent studies have revealed the involvement of IFT particle subunits in organogenesis and spermatogenesis.In this review,we discuss new concepts concerning the molecular functions of IFT protein IFT25 and how its interactions with other IFT particle subunits are involved in mammalian development and fertility.展开更多
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)+1 种基金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)。
文摘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.
基金supported by the Natural Science Foundation of Hubei Province(Excellent Youth Foundation,No.2018CFA040)the Outstanding Young and Middle-aged Technology Innovation Team Project of the Hubei Provincial Department of Education(No.T2020003)+1 种基金NIH grant(No.HD076257)Wayne State University Start-up fund.
文摘Cilium,an organelle with a unique proteome and organization,protruding from the cell surface,generally serves as a force generator and signaling compartment.During ciliogenesis,ciliary proteins are synthesized in cytoplasm and transported into cilia by intraflagellar transport(IFT)particles,where the inner counterparts undergo reverse trafficking.The homeostasis of IFT plays a key role in cilial structure assembly and signaling transduction.Much progress has been made on the mechanisms and functions of IFT;however,recent studies have revealed the involvement of IFT particle subunits in organogenesis and spermatogenesis.In this review,we discuss new concepts concerning the molecular functions of IFT protein IFT25 and how its interactions with other IFT particle subunits are involved in mammalian development and fertility.
