The published article titled“Silencing of lncRNA CCDC26 Restrains the Growth and Migration of Glioma Cells In Vitro and In Vivo via Targeting miR-203”has been retracted fromOncology Research,Vol.26,No.8,2018,pp.1143...The published article titled“Silencing of lncRNA CCDC26 Restrains the Growth and Migration of Glioma Cells In Vitro and In Vivo via Targeting miR-203”has been retracted fromOncology Research,Vol.26,No.8,2018,pp.1143–1154.展开更多
Laterality is a crucial physiological process intricately linked to the cilium-centrosome complex during embryo development.Defects in the process can result in severe organ mispositioning.Coiled-coil domain containin...Laterality is a crucial physiological process intricately linked to the cilium-centrosome complex during embryo development.Defects in the process can result in severe organ mispositioning.Coiled-coil domain containing 141(CCDC141)has been previously known as a centrosome-related gene,but its role in left-right(LR)asymmetry has not been characterized.In this study,we utilize the zebrafish model and human exome analysis to elucidate the function of ccdc141 in laterality defects.The knockdown of ccdc141 in zebrafish disrupts early LR signaling pathways,cilia function,and Kupffer's vesicle formation.Unlike ccdc141-knockdown embryos exhibiting aberrant LR patterns,ccdc141-null mutants show no apparent abnormality,suggesting a genetic compensation response effect.In parallel,we observe a marked reduction inα-tubulin acetylation levels in the ccdc141 crispants.The treatment with histone deacetylase(HDAC)inhibitors,particularly the HDAC6 inhibitor,rescues the ccdc141 crispant phenotypes.Furthermore,exome analysis of 70 patients with laterality defects reveals an increased burden of CCDC141 mutations,with in-vivo studies verifying the pathogenicity of the patient mutation CCDC141-R123G.Our findings highlight the critical role of ccdc141 in ciliogenesis and demonstrate that CCDC141 mutations lead to abnormal LR patterns,identifying it as a candidate gene for laterality defects.展开更多
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
Male infertility is a worldwide health issue,affecting 8%–12%of the global population.Oligoasthenoteratozoospermia(OAT)represents a severe type of male infertility,characterized by reduced sperm count and motility an...Male infertility is a worldwide health issue,affecting 8%–12%of the global population.Oligoasthenoteratozoospermia(OAT)represents a severe type of male infertility,characterized by reduced sperm count and motility and an increased frequency of sperm with aberrant morphology.Using whole-exome sequencing,this study identified a novel missense mutation(c.848C>A,p.A283E)in the coiled-coil domain-containing 34 gene(CCDC34)in a consanguineous Pakistani family.This rare mutation was predicted to be deleterious and to affect the protein stability.Hematoxylin and eosin staining of spermatozoa from the patient with OAT revealed multiple morphological abnormalities of the flagella and transmission electron microscopy indicated axonemal ultrastructural defects with a lack of outer dynein arms.These findings indicated that CCDC34 plays a role in maintaining the axonemal ultrastructure and the assembly or stability of the outer dynein arms,thus expanding the phenotypic spectrum of CCDC34 missense mutations.展开更多
The structural integrity of the sperm flagellum is essential for proper sperm function.Flagellar defects can result in male infertility,yet the precise mechanisms underlying this relationship are not fully understood....The structural integrity of the sperm flagellum is essential for proper sperm function.Flagellar defects can result in male infertility,yet the precise mechanisms underlying this relationship are not fully understood.CCDC181,a coiled-coil domain-containing protein,is known to localize on sperm flagella and at the basal regions of motile cilia.Despite this knowledge,the specific functions of CCDC181 in flagellum biogenesis remain unclear.In this study,Ccdc181 knockout mice were generated.The absence of CCDC181 led to defective sperm head shaping and flagellum formation.Furthermore,the Ccdc181 knockout mice exhibited extremely low sperm counts,grossly aberrant sperm morphologies,markedly diminished sperm motility,and typical multiple morphological abnormalities of the flagella(MMAF).Additionally,an interaction between CCDC181 and the MMAF-related protein LRRC46 was identified,with CCDC181 regulating the localization of LRRC46 within sperm flagella.These findings suggest that CCDC181 plays a crucial role in both manchette formation and sperm flagellum biogenesis.展开更多
文摘The published article titled“Silencing of lncRNA CCDC26 Restrains the Growth and Migration of Glioma Cells In Vitro and In Vivo via Targeting miR-203”has been retracted fromOncology Research,Vol.26,No.8,2018,pp.1143–1154.
基金supported by the National Natural Science Foundation of China(81970264).
文摘Laterality is a crucial physiological process intricately linked to the cilium-centrosome complex during embryo development.Defects in the process can result in severe organ mispositioning.Coiled-coil domain containing 141(CCDC141)has been previously known as a centrosome-related gene,but its role in left-right(LR)asymmetry has not been characterized.In this study,we utilize the zebrafish model and human exome analysis to elucidate the function of ccdc141 in laterality defects.The knockdown of ccdc141 in zebrafish disrupts early LR signaling pathways,cilia function,and Kupffer's vesicle formation.Unlike ccdc141-knockdown embryos exhibiting aberrant LR patterns,ccdc141-null mutants show no apparent abnormality,suggesting a genetic compensation response effect.In parallel,we observe a marked reduction inα-tubulin acetylation levels in the ccdc141 crispants.The treatment with histone deacetylase(HDAC)inhibitors,particularly the HDAC6 inhibitor,rescues the ccdc141 crispant phenotypes.Furthermore,exome analysis of 70 patients with laterality defects reveals an increased burden of CCDC141 mutations,with in-vivo studies verifying the pathogenicity of the patient mutation CCDC141-R123G.Our findings highlight the critical role of ccdc141 in ciliogenesis and demonstrate that CCDC141 mutations lead to abnormal LR patterns,identifying it as a candidate gene for laterality defects.
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 National Natural Science Foundation of China(No.82071709,No.32070850,and No.82171601)the National Key Research and Developmental Program of China(2022YFC2702601 and 2022YFA0806303)the Joint Fund for New Medicine of USTC(YD9100002034).
文摘Male infertility is a worldwide health issue,affecting 8%–12%of the global population.Oligoasthenoteratozoospermia(OAT)represents a severe type of male infertility,characterized by reduced sperm count and motility and an increased frequency of sperm with aberrant morphology.Using whole-exome sequencing,this study identified a novel missense mutation(c.848C>A,p.A283E)in the coiled-coil domain-containing 34 gene(CCDC34)in a consanguineous Pakistani family.This rare mutation was predicted to be deleterious and to affect the protein stability.Hematoxylin and eosin staining of spermatozoa from the patient with OAT revealed multiple morphological abnormalities of the flagella and transmission electron microscopy indicated axonemal ultrastructural defects with a lack of outer dynein arms.These findings indicated that CCDC34 plays a role in maintaining the axonemal ultrastructure and the assembly or stability of the outer dynein arms,thus expanding the phenotypic spectrum of CCDC34 missense mutations.
基金supported by the National Natural Science Foundation of China(82071709,81971446,82171599,82374212)Global Select Project(DJK-LX-2022010)of the Institute of Health and Medicine,Hefei Comprehensive National Science CenterJoint Fund for New Medicine of USTC(YD9100002034)。
文摘The structural integrity of the sperm flagellum is essential for proper sperm function.Flagellar defects can result in male infertility,yet the precise mechanisms underlying this relationship are not fully understood.CCDC181,a coiled-coil domain-containing protein,is known to localize on sperm flagella and at the basal regions of motile cilia.Despite this knowledge,the specific functions of CCDC181 in flagellum biogenesis remain unclear.In this study,Ccdc181 knockout mice were generated.The absence of CCDC181 led to defective sperm head shaping and flagellum formation.Furthermore,the Ccdc181 knockout mice exhibited extremely low sperm counts,grossly aberrant sperm morphologies,markedly diminished sperm motility,and typical multiple morphological abnormalities of the flagella(MMAF).Additionally,an interaction between CCDC181 and the MMAF-related protein LRRC46 was identified,with CCDC181 regulating the localization of LRRC46 within sperm flagella.These findings suggest that CCDC181 plays a crucial role in both manchette formation and sperm flagellum biogenesis.
