BACKGROUND Cockayne syndrome(CS)is a rare inherited disease characterized by progressive motor symptoms including muscle weakness,joint contracture,ataxia,and spasticity.Botulinum neurotoxin type A has been used for c...BACKGROUND Cockayne syndrome(CS)is a rare inherited disease characterized by progressive motor symptoms including muscle weakness,joint contracture,ataxia,and spasticity.Botulinum neurotoxin type A has been used for conditions such as dystonia and spasticity,but it has rarely been used in patients with CS.CASE SUMMARY We report a 6-year-and-9-mo old girl diagnosed with CS who received an injection of botulinum neurotoxin type A to manage her difficulty with walking.A total dose of 210 units of botulinum neurotoxin type A was administered into the bilateral tibialis posterior and gastrocnemius muscles.To evaluate the treatment effects on spasticity,joint contracture,pain,and ataxia,measurement tools including the Modified Ashworth Scale,the passive range of motion,the Faces Pain Scale-Revised,and the Scale for the Assessment and Rating of Ataxia,were employed.The first week after the injection,the Modified Ashworth Scale score for the plantar flexors and foot invertors improved bilaterally,along with advancements in the passive range of motion of the bilateral ankles and a lower score for the Faces Pain Scale-Revised.These treatment effects persisted to the 8th week post-injection,but returned to baseline values at the 12th week post-injection,except for the pain scale.CONCLUSION Botulinum toxin injection can thus be considered as a treatment option for lower extremity spasticity,joint contracture,and pain derived from CS.展开更多
BACKGROUND Leigh syndrome(LS)is one of the most common mitochondrial diseases in infants and children.LS often manifests as early-onset with delayed phenotypic development.However,late-onset LS with normal development...BACKGROUND Leigh syndrome(LS)is one of the most common mitochondrial diseases in infants and children.LS often manifests as early-onset with delayed phenotypic development.However,late-onset LS with normal development and white matter lesions in the brain is rarely reported,thereby highlighting the phenotypic variability of LS expression.CASE SUMMARY We report a 12-year-old boy who presented with an unusual late-onset and fulminant form of LS that is maternally inherited without developmental delay.The patient was admitted to the hospital with symptoms of ptosis and somnolence,and died within 2 mo.Analysis of peripheral blood leukocytes showed a homoplasmic m.9176T>C mutation in the patient.Magnetic resonance imaging also revealed lesions in bilateral white matter as well as symmetrical lesions in the basal ganglia and brain stem.The patient was diagnosed with LS.The patient was treated with vitamin C,vitamin D,and adenosine-triphosphate.The patient died within 2 mo of hospital admission.CONCLUSION LS can present in both infants and older children with different phenotypes.展开更多
Cockayne syndrome(CS)group B(CSB),which results from mutations in the excision repair cross-complementation group 6(ERCC6)genes,which produce CSB protein,is an autosomal recessive disease characterized by multiple pro...Cockayne syndrome(CS)group B(CSB),which results from mutations in the excision repair cross-complementation group 6(ERCC6)genes,which produce CSB protein,is an autosomal recessive disease characterized by multiple progressive disorders including growth failure,microcephaly,skin photosensitivity,and premature aging.Clinical data show that brain atrophy,demyelination,and calcification are the main neurological manifestations of CS,which progress with time.Neuronal loss and calcification occur in various brain areas,particularly the cerebellum and basal ganglia,resulting in dyskinesia,ataxia,and limb tremors in CSB patients.However,the understanding of neurodevelopmental defects in CS has been constrained by the lack of significant neurodevelopmental and functional abnormalities observed in CSB-deficient mice.In this review,we focus on elucidating the protein structure and distribution of CSB and delve into the impact of CSB mutations on the development and function of the nervous system.In addition,we provide an overview of research models that have been instrumental in exploring CS disorders,with a forward-looking perspective on the substantial contributions that brain organoids are poised to further advance this field.展开更多
Cockayne syndrome(CS)is a rare autosomal recessive inherited disorder characterized by a variety of clinical features,including increased sensitivity to sunlight,progressive neurological abnormalities,and the appearan...Cockayne syndrome(CS)is a rare autosomal recessive inherited disorder characterized by a variety of clinical features,including increased sensitivity to sunlight,progressive neurological abnormalities,and the appearance of premature aging.However,the pathogenesis of CS remains unclear due to the limitations of current disease models.Here,we generate integration-free induced pluripotent stem cells(iPSCs)from fibroblasts from a CS patient bearing mutations in CSB/ERCC6 gene and further derive isogenic genecorrected CS-iPSCs(GC-iPSCs)using the CRISPR/Cas9 system.CS-associated phenotypic defects are recapitulated in CS-iPSC-derived mesenchymal stem cells(MSCs)and neural stem cells(NSCs),both of which display increased susceptibility to DNA damage stress.Premature aging defects in CS-MSCs are rescued by the targeted correction of mutant ERCC6.We next map the transcriptomic landscapes in CS-iPSCs and GC-iPSCs and their somatic stem cell derivatives(MSCs and NSCs)in the absence or presence of ultraviolet(UV)and replicative stresses,revealing that defects in DNA repair account for CS pathologies.Moreover,we generate autologous GC-MSCs free of pathogenic mutation under a cGMP(Current Good Manufacturing Practice)-compliant condition,which hold potential for use as improved biomaterials for future stem cell replacement therapy for CS.Collectively,our models demonstrate novel disease features and molecular mechanisms and lay a foundation for the development of novel therapeutic strategies to treat CS.展开更多
The encounter of elongating RNA polymerase Ⅱ （RNAPⅡo） with DNA lesions has severe consequences for the cell as this event provides a strong signal for P53-dependent apoptosis and cell cycle arrest. To counteract p...The encounter of elongating RNA polymerase Ⅱ （RNAPⅡo） with DNA lesions has severe consequences for the cell as this event provides a strong signal for P53-dependent apoptosis and cell cycle arrest. To counteract prolonged blockage of transcription, the cell removes the RNAPⅡo-blocking DNA lesions by transcription-coupled repair （TC-NER）, a specialized subpathway of nucleotide excision repair （NER）. Exposure of mice to UVB light or chemicals has elucidated that TC-NER is a critical survival pathway protecting against acute toxic and long-term effects （cancer） of genotoxic exposure. Deficiency in TC-NER is associated with mutations in the CSA and CSB genes giving rise to the rare human disorder Cockayne syndrome （CS）. Recent data suggest that CSA and CSB play differential roles in mammalian TC-NER： CSB as a repair coupling factor to attract NER proteins, chromatin remodellers and the CSA- E3-ubiquitin ligase complex to the stalled RNAPⅡo. CSA is dispensable for attraction of NER proteins, yet in cooperation with CSB is required to recruit XAB2, the nucleosomal binding protein HMGN1 and TFⅡS. The emerging picture of TC-NER is complex： repair of transcription-blocking lesions occurs without displacement of the DNA damage-stalled RNAPⅡo, and requires at least two essential assembly factors （CSA and CSB）, the core NER factors （except for XPC-RAD23B）, and TC-NER specific factors. These and yet unidentified proteins will accomplish not only efficient repair of transcription-blocking lesions, but are also likely to contribute to DNA damage signalling events.展开更多
Background Cockayne syndrome （CS） is a rare human genetic disorder characterized by increased UV sensitivity, developmental abnormalities and premature aging. Cells isolated from individuals with CS have a defect in...Background Cockayne syndrome （CS） is a rare human genetic disorder characterized by increased UV sensitivity, developmental abnormalities and premature aging. Cells isolated from individuals with CS have a defect in transcription-coupled DNA repair. Despite the repair defect, there is no any increased risk of spontaneous or UV-induced cancer for CS individuals. The strategy of RNA interfering was used here to explore the potential radiosensitizing and anticancer activity of targeting CS group B （CSB） gene. Methods The vectors encoding CSB-specific siRNAs were constructed by inserting duplex siRNA encoding oligonucleotides into the plasmid P^silencer TM 3.1. The cell lines expressing the CSB-siRNA were generated from HeLa cells transfected with the above vectors. Colony-forming ability was used to assay cell survival. Cell cycle was analyzed by FACScan flow cytometry. The apoptosis was measured by detecting the accumulation of sub-G1 population as well as by fluorescence staining assay. Reverse transcriptase polymerase chain reaction （RT-PCR） was used to semi-quantify mRNA expression. Protein level was detected by Western blotting analysis. Results Two constructs encoding CSB-specific siRNA were generated, both of them resulted in remarkable suppression on CSB expression in HeLa cells, and led to an increased sensitivity to T-ray and UV light. siRNA-mediated silencing of CSB decreased cell proliferation rate, increased spontaneous apoptosis as well as the occurrence of UV- or cisplatin-induced apoptosis by 2 to 3.5 fold. A significant S phase blockage and a remarkable reduction of G1 population were induced in control HeLa cells at 18 hours after being exposed to 10 J/m^2 of UV light. The S phase blockage was also observed in UV-irradiated CSB-siRNA transfected HeLa cells, but the extent of increased S phase population was lower than that in the UV-irradiated control cells. No or a relative weak reduction on G1 phase population was observed in UV-irradiated CSB-siRNA transfected HeLa cells. In addition, siRNA-mediated silencing of CSB promoted the elimination of G2/M phase cells after UV light radiation. Conclusions siRNA-mediated silencing of CSB causes cells to proliferate more slowly, sensitize cells to genotoxicants, and modify UV radiation-induced cell cycle changes, siRNA-mediated inactivation of CSB could be an attractive strategy for ameliorating cancer therapy, which can be fulfilled via the combination of gene therapy and sensitization of radiotherapy or chemotherapy.展开更多
文摘BACKGROUND Cockayne syndrome(CS)is a rare inherited disease characterized by progressive motor symptoms including muscle weakness,joint contracture,ataxia,and spasticity.Botulinum neurotoxin type A has been used for conditions such as dystonia and spasticity,but it has rarely been used in patients with CS.CASE SUMMARY We report a 6-year-and-9-mo old girl diagnosed with CS who received an injection of botulinum neurotoxin type A to manage her difficulty with walking.A total dose of 210 units of botulinum neurotoxin type A was administered into the bilateral tibialis posterior and gastrocnemius muscles.To evaluate the treatment effects on spasticity,joint contracture,pain,and ataxia,measurement tools including the Modified Ashworth Scale,the passive range of motion,the Faces Pain Scale-Revised,and the Scale for the Assessment and Rating of Ataxia,were employed.The first week after the injection,the Modified Ashworth Scale score for the plantar flexors and foot invertors improved bilaterally,along with advancements in the passive range of motion of the bilateral ankles and a lower score for the Faces Pain Scale-Revised.These treatment effects persisted to the 8th week post-injection,but returned to baseline values at the 12th week post-injection,except for the pain scale.CONCLUSION Botulinum toxin injection can thus be considered as a treatment option for lower extremity spasticity,joint contracture,and pain derived from CS.
基金the National Natural Science Foundation of China,No.81801284 and No.81771396.
文摘BACKGROUND Leigh syndrome(LS)is one of the most common mitochondrial diseases in infants and children.LS often manifests as early-onset with delayed phenotypic development.However,late-onset LS with normal development and white matter lesions in the brain is rarely reported,thereby highlighting the phenotypic variability of LS expression.CASE SUMMARY We report a 12-year-old boy who presented with an unusual late-onset and fulminant form of LS that is maternally inherited without developmental delay.The patient was admitted to the hospital with symptoms of ptosis and somnolence,and died within 2 mo.Analysis of peripheral blood leukocytes showed a homoplasmic m.9176T>C mutation in the patient.Magnetic resonance imaging also revealed lesions in bilateral white matter as well as symmetrical lesions in the basal ganglia and brain stem.The patient was diagnosed with LS.The patient was treated with vitamin C,vitamin D,and adenosine-triphosphate.The patient died within 2 mo of hospital admission.CONCLUSION LS can present in both infants and older children with different phenotypes.
基金supported by the National Natural Science Foundation of China(Nos.32000692 and 32200816).
文摘Cockayne syndrome(CS)group B(CSB),which results from mutations in the excision repair cross-complementation group 6(ERCC6)genes,which produce CSB protein,is an autosomal recessive disease characterized by multiple progressive disorders including growth failure,microcephaly,skin photosensitivity,and premature aging.Clinical data show that brain atrophy,demyelination,and calcification are the main neurological manifestations of CS,which progress with time.Neuronal loss and calcification occur in various brain areas,particularly the cerebellum and basal ganglia,resulting in dyskinesia,ataxia,and limb tremors in CSB patients.However,the understanding of neurodevelopmental defects in CS has been constrained by the lack of significant neurodevelopmental and functional abnormalities observed in CSB-deficient mice.In this review,we focus on elucidating the protein structure and distribution of CSB and delve into the impact of CSB mutations on the development and function of the nervous system.In addition,we provide an overview of research models that have been instrumental in exploring CS disorders,with a forward-looking perspective on the substantial contributions that brain organoids are poised to further advance this field.
基金supported by the National Key Research and Development Program of China(2018YFC2000100)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010100)+5 种基金the National Key Research and Development Program of China(2018YFA0107203,2017YFA0103304,2017YFA0102802,2016YFC1000601,2015CB 964800,2014CB910503,and 2018YFA0108500)the National Natural Science Foundation of China(Grant Nos.81625009,81330008,91749202,91749123,31671429,81671377,81771515,31601109,31601158,81701388,81601233,81822018,81801399,31801010,81801370,81861168034,81571400,and 81771580)the Program of the Beijing Municipal Science and TechnologyCommission(Z151100003915072)the Key Research Program of the Chinese Academy of Sciences(KJZDEWTZ-L05)the Beijing Municipal Commission of Health and Family Planning(PXM2018_026283_000002)the Advanced Innovation Center for Human Brain Protection(117212,3500-1192012).
文摘Cockayne syndrome(CS)is a rare autosomal recessive inherited disorder characterized by a variety of clinical features,including increased sensitivity to sunlight,progressive neurological abnormalities,and the appearance of premature aging.However,the pathogenesis of CS remains unclear due to the limitations of current disease models.Here,we generate integration-free induced pluripotent stem cells(iPSCs)from fibroblasts from a CS patient bearing mutations in CSB/ERCC6 gene and further derive isogenic genecorrected CS-iPSCs(GC-iPSCs)using the CRISPR/Cas9 system.CS-associated phenotypic defects are recapitulated in CS-iPSC-derived mesenchymal stem cells(MSCs)and neural stem cells(NSCs),both of which display increased susceptibility to DNA damage stress.Premature aging defects in CS-MSCs are rescued by the targeted correction of mutant ERCC6.We next map the transcriptomic landscapes in CS-iPSCs and GC-iPSCs and their somatic stem cell derivatives(MSCs and NSCs)in the absence or presence of ultraviolet(UV)and replicative stresses,revealing that defects in DNA repair account for CS pathologies.Moreover,we generate autologous GC-MSCs free of pathogenic mutation under a cGMP(Current Good Manufacturing Practice)-compliant condition,which hold potential for use as improved biomaterials for future stem cell replacement therapy for CS.Collectively,our models demonstrate novel disease features and molecular mechanisms and lay a foundation for the development of novel therapeutic strategies to treat CS.
文摘The encounter of elongating RNA polymerase Ⅱ （RNAPⅡo） with DNA lesions has severe consequences for the cell as this event provides a strong signal for P53-dependent apoptosis and cell cycle arrest. To counteract prolonged blockage of transcription, the cell removes the RNAPⅡo-blocking DNA lesions by transcription-coupled repair （TC-NER）, a specialized subpathway of nucleotide excision repair （NER）. Exposure of mice to UVB light or chemicals has elucidated that TC-NER is a critical survival pathway protecting against acute toxic and long-term effects （cancer） of genotoxic exposure. Deficiency in TC-NER is associated with mutations in the CSA and CSB genes giving rise to the rare human disorder Cockayne syndrome （CS）. Recent data suggest that CSA and CSB play differential roles in mammalian TC-NER： CSB as a repair coupling factor to attract NER proteins, chromatin remodellers and the CSA- E3-ubiquitin ligase complex to the stalled RNAPⅡo. CSA is dispensable for attraction of NER proteins, yet in cooperation with CSB is required to recruit XAB2, the nucleosomal binding protein HMGN1 and TFⅡS. The emerging picture of TC-NER is complex： repair of transcription-blocking lesions occurs without displacement of the DNA damage-stalled RNAPⅡo, and requires at least two essential assembly factors （CSA and CSB）, the core NER factors （except for XPC-RAD23B）, and TC-NER specific factors. These and yet unidentified proteins will accomplish not only efficient repair of transcription-blocking lesions, but are also likely to contribute to DNA damage signalling events.
基金This work was supported by the grants from Chinese National High Technology "863" Programs (No. 2004AA221160) and National Natural Science Foundation of China (No. 30270423).
文摘Background Cockayne syndrome （CS） is a rare human genetic disorder characterized by increased UV sensitivity, developmental abnormalities and premature aging. Cells isolated from individuals with CS have a defect in transcription-coupled DNA repair. Despite the repair defect, there is no any increased risk of spontaneous or UV-induced cancer for CS individuals. The strategy of RNA interfering was used here to explore the potential radiosensitizing and anticancer activity of targeting CS group B （CSB） gene. Methods The vectors encoding CSB-specific siRNAs were constructed by inserting duplex siRNA encoding oligonucleotides into the plasmid P^silencer TM 3.1. The cell lines expressing the CSB-siRNA were generated from HeLa cells transfected with the above vectors. Colony-forming ability was used to assay cell survival. Cell cycle was analyzed by FACScan flow cytometry. The apoptosis was measured by detecting the accumulation of sub-G1 population as well as by fluorescence staining assay. Reverse transcriptase polymerase chain reaction （RT-PCR） was used to semi-quantify mRNA expression. Protein level was detected by Western blotting analysis. Results Two constructs encoding CSB-specific siRNA were generated, both of them resulted in remarkable suppression on CSB expression in HeLa cells, and led to an increased sensitivity to T-ray and UV light. siRNA-mediated silencing of CSB decreased cell proliferation rate, increased spontaneous apoptosis as well as the occurrence of UV- or cisplatin-induced apoptosis by 2 to 3.5 fold. A significant S phase blockage and a remarkable reduction of G1 population were induced in control HeLa cells at 18 hours after being exposed to 10 J/m^2 of UV light. The S phase blockage was also observed in UV-irradiated CSB-siRNA transfected HeLa cells, but the extent of increased S phase population was lower than that in the UV-irradiated control cells. No or a relative weak reduction on G1 phase population was observed in UV-irradiated CSB-siRNA transfected HeLa cells. In addition, siRNA-mediated silencing of CSB promoted the elimination of G2/M phase cells after UV light radiation. Conclusions siRNA-mediated silencing of CSB causes cells to proliferate more slowly, sensitize cells to genotoxicants, and modify UV radiation-induced cell cycle changes, siRNA-mediated inactivation of CSB could be an attractive strategy for ameliorating cancer therapy, which can be fulfilled via the combination of gene therapy and sensitization of radiotherapy or chemotherapy.
