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Compound heterozygous mutation of AFG3L2 causes autosomal recessive spinocerebellar ataxia through mitochondrial impairment and MICU1 mediated Caoverload

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Science China Life Sciences 2024年

作者： hongyu Li Qingwen Ma Yan Xue Linlin Cai Liwen Bao Lei hong Yitao Zeng Shuzhen huang richard h.finnell Fanyi Zeng Shanghai Institute of Medical Genetics Shanghai Children's Hospital Shanghai Jiao Tong University School of Medicine Department of histo-Embryology Genetics and Developmental Biology Shanghai Jiao Tong University School of Medicine NhC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology Shanghai Key Laboratory of Embryo and Reproduction Engineering Center for Precision Environmental health Baylor College of Medicine School of Pharmacy Macau University of Science and Technology

Autosomal recessive spinocerebellar ataxias（SCARs） are one of the most common neurodegenerative diseases characterized by progressive ataxia. Although SCARs are known to be caused by mutations in multiple genes, there are still many cases that go undiagnosed or are misdiagnosed. In this study, we presented a SCAR patient, and identified a probable novel pathogenic mutation（c.1A>G, p.M1V） in the AFG3L2 start codon. The proband's genotype included heterozygous mutations of the compound AFG3L2(p.[M1V]; [R632X]（c.[1A>G];[1894.C>T]）), which were inherited from the father（c.1A>G, p.M1V） and mother（c.1894C>T, p.R632X）. Functional studies performed on hiPSCs（human induced pluripotent stem cells） generated from the patients and hEK293T cells showed that the mutations impair mitochondrial function and the unbalanced expression of AFG3L2 mRNA and protein levels. Furthermore, this novel mutation resulted in the degradation of the protein and the reduction of the stability of the AFG3L2 protein, and MCU（mitochondrial calcium uniporter） complex mediated Ca2+overload.

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A mutation in TBXT causes congenital vertebral malformations in humans and mice

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Journal of Genetics and Genomics 2024年第4期51卷 433-442页

作者： Shuxia Chen Yunping Lei Yajun Yang Chennan Liu Lele Kuang Li Jin richard hfinnell Xueyan Yang hongyan Wang Obstetrics and Gynecology hospital State Key Laboratory of Genetic Engineering at School of Life SciencesKey Laboratory of Reproduction Regulation of NPFPCInstitute of Reproduction and DevelopmentFudan UniversityShanghai 200438China Shanghai Key Laboratory of Metabolic Remodeling and health Institute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China Center for Precision Environmental health Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonTX 77030USA MOE Key Laboratory of Contemporary Anthropology School of Life SciencesFudan UniversityShanghai 200438China Department of Assisted Reproduction Xinhua HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200092China Children’s hospital Fudan University399 Wanyuan RoadShanghai 201102China

T-box transcription factor T(TBXT;T)is required for mesodermal formation and axial skeletal *** it has been extensively studied in various model organisms,human congenital vertebral malformations(CVMs)involving T are not well ***,we report a family with 15 CVM patients distributed across 4 *** affected individuals carry a heterozygous mutation,T c.596A>G(p.Q199R),which is not found in unaffected family members,indicating co-segregation of the genotype and *** vitro assays show that T p.Q199R increases the nucleocytoplasmic ratio and enhances its DNA-binding affinity,but reduces its transcriptional activity compared to the *** determine the pathogenicity of this mutation in vivo,we generated a Q199R knock-in mouse model that recapitulates the human CVM *** heterozygous Q199R mice show subtle kinked or shortened tails,while homozygous mice exhibit tail filaments and severe vertebral ***,we show that the Q199R mutation in T causes CVM in humans and mice,providing previously unreported evidence supporting the function of T in the genetic etiology of human CVM.

关键词： Congenital vertebral malformation TBXT T gene Loss-of-function mutation

Endorepellin和neurexin互作促进神经上皮细胞自噬并维持正常神经管发育

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Science Bulletin 2024年第14期69卷 2260-2272页

作者：卢磊白梅竹郑煜芳王修坤陈仲中彭瑞 richard h.finnell 赵同金李承涛吴波雷云平李劲松王红艳 Shanghai Key Laboratory of Metabolic Remodeling and health Institute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China Obstetrics&Gynecology hospital State Key Laboratory of Genetic EngineeringFudan UniversityShanghai 200032China Key Laboratory of Multi-Cell Systems Shanghai Key Laboratory of Molecular AndrologyCAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai 200031China Obstetrics&Gynecology hospital The Institute of Obstetrics and GynecologyFudan UniversityShanghai 200090China Center for Precision Environmental health Department of Molecular and Cellular BiologyBaylor College of MedicineHouston 77031USA Shanghai Medical College Fudan UniversityShanghai 200032China Prenatal Diagnosis Center of Shenzhen Maternity&Child healthcare hospital Shenzhen 518028China Children’s hospital Fudan UniversityShanghai 201102China

heparan sulfate proteoglycan 2(hSPG2)gene encodes the matrix protein Perlecan,and genetic inactivation of this gene creates mice that are embryonic lethal with severe neural tube defects(NTDs).We discovered rare genetic variants of hSPG2 in 10%cases compared to only 4%in controls among a cohort of 369 ***,a peptide cleaved from the domain V of Perlecan,is known to promote angiogenesis and autophagy in endothelial *** roles of enderepellin in neurodevelopment remain unclear so *** study revealed that endorepellin can migrate to the neuroepithelial cells and then be recognized and bind with the neuroepithelia receptor neurexin in *** the endocytic pathway,the interaction of endorepellin and neurexin physiologically triggers autophagy and appropriately modulates the differentiation of neural stem cells into neurons as a blocker,which is necessary for normal neural tube *** created knock-in(KI)mouse models with human-derived hSPG2 variants,using sperm-like stem cells that had been genetically edited by CRISPR/*** realized that any hSPG2 variants that affected the function of endorepellin were considered pathogenic causal variants for human NTDs given that the severe NTD phenotypes exhibited by these KI embryos occurred in a significantly higher response frequency compared to wildtype *** study provides a paradigm for effectively confirming pathogenic mutations in other genetic ***,we demonstrated that using autophagy inhibitors at a cellular level can repress neuronal ***,autophagy agonists may prevent NTDs resulting from failed autophagy maintenance and neuronal over-differentiation caused by deleterious endorepellin variants.

关键词： Neural tube defects Androgenetic haploid embryonic stem cells Basement membrane Neural stem cell Autophagy

Executive Editor-in-Chief’s introduction for this Special Issue

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Reproductive and Developmental Medicine 2022年第1期6卷 65-66页

作者： richard h.finnell Center for Precision Environmental health Baylor College of MedicineOne Baylor PlazaBCM 946HoustonTX 77030-411USA

Dear Colleagues,As an Executive Editor-in-Chief,I have edited this Special Issue(SI),entitled “Birth Defects:Issues and Advances in 2022”in the journal Reproductive and Developmental Medicine(RDM,ISSN:2096-2924,CN:10-1442/R),the first ever English journal in the field of reproductive medicine and developmental biology in China's *** its launch in 2017,RDM has been dedicated to providing a good platform for academic exchanges among scientists,both at home and abroad.

关键词： journal mainland Executive

homozygous Mutation in the MThFS Gene May Contribute to the Development of Cerebral Folate Deficiency Syndrome

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Reproductive and Developmental Medicine 2020年第2期4卷 72-77页

作者： Dharaniya Sakthivel Yunping Lei Xuanye Cao richard h.finnell Center for Precision Environmental health Baylor College of MedicineHoustonTexas 77030-3411USA Department of Molecular and human Genetics Baylor College of MedicineHoustonTexas 77030-3411USA Department of Molecular and Cellular Biology Baylor College of MedicineHoustonTexas 77030-3411USA Department of Medicine Baylor College of MedicineHoustonTexas 77030-3411USA

Objective:The purpose of this study was to examine the role of rare variants in the one-carbon metabolic pathway in the etiology of the cerebral folate deficiency(CFD)*** CFD syndrome is a neurometabolic syndrome identified by low concentrations of 5-methyltetrahydrofolate(5-MThF)in the cerebrospinal fluid(CSF)in spite of near-normal peripheral folate levels resulting in neurodevelopmental ***:The localized folate metabolism impairments in CFD are thought to be either the result of mutations in genes responsible for folate transport or folate turnover through *** that have been previously implicated in the etiology of CFD include folate receptor alpha-1(FOLR1),dihydrofolate reductase,proton-coupled folate transporter,and *** performed whole-exome sequencing(WES)analysis of a CFD patient that revealed 99 novel missense mutations,of which 21 were classified as damaging mutations through the Poly-Phen2 prediction *** vitro functional studies were conducted by transient transfection of wild-type and mutant MThFS into hEK293T cells to determine the impact of the variants on enzyme ***:Of the damaging variants identified in the WES studies,we focused on the gene coding for the enzyme 5,10-methenyl-tetrahydrofolate synthetase(MThFS).This enzyme catalyzes the production of methenyl ThF which is subsequently converted to *** CFD patient described within was found to carry a homozygous mutation,c.101G>T(p.R34L,rs200058464)in MThFS,while the parents of the proband are heterozygotes for the MThFS gene,and the healthy sibling is not a ***:The mutant allele displayed a 50%reduction in luciferase activity(Phat homozygous loss of the MThFS gene may play a significant role in the development of CFD.

关键词： Cerebral Folate Deficiency Syndrome MThFS Intellectual Disability

DVL mutations identified from human neural tube defects and Dandy-Walker malformation obstruct the Wnt signaling pathway

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Journal of Genetics and Genomics 2020年第6期47卷 301-310页

作者： Lingling Liu Weiqi Liu Yan Shi Ling Li Yunqian Gao Yunping Lei richard finnell Ting Zhang Feng Zhang Li Jin huili Li Wufan Tao hongyan Wang Obstetrics and Gynecology hospital State Key Laboratory of Genetic Engineering at School of Life SciencesFudan UniversityShanghai200011China NhC Key Lab of Reproduction(Shanghai Institute of Planned Parenthood Research) Institute of Reproduction and DevelopmentFudan UniversityShanghai200032China Departments of Molecular and Cellular Biology and Medicine Baylor College of MedicineHoustonTX77030USA Capital Institute of Pediatrics Beijing100020China Children's hospital and Institutes of Biomedical Sciences Fudan UniversityShanghai200032China Molecular Cellular and Developmental BiologyUniversity of Colorado BoulderBoulderCO 80309USA Insititute of Developmental Biology and Molecular Medicine Fudan UniversityShanghai200433China

Wnt signaling pathways,including the canonical Wnt/β-catenin pathway,planar cell polarity pathway,and Wnt/Ca2+signaling pathway,play important roles in neural development during embryonic *** DVL genes encode the hub proteins for Wnt signaling *** mutations in DVL2 and DVL3 were identified from patients with neural tube defects(NTDs),but their functions in the pathogenesis of human neural diseases remain ***,we sequenced the coding regions of three DVL genes in 176 stillborn or miscarried fetuses with NTDs or Dandy-Walker malformation(DWM)and 480 adult controls from a han Chinese *** rare mutations were identified:DVL1 p.R558 h,DVL1 p.R606 C,DVL2 p.R633 W,and DVL3 p.R222 *** assess the effect of these mutations on NTDs and DWM,various functional analyses such as luciferase reporter assay,stress fiber formation,and in vivo teratogenic assay were *** results showed that the DVL2 p.R633 W mutation destabilized DVL2 protein and upregulated activities for all three Wnt signalings(Wnt/β-catenin signaling,Wnt/planar cell polarity signaling,and Wnt/Ca2+signaling)in mammalian *** contrast,DVL1 mutants(DVL1 p.R558 h and DVL1 p.R606 C)decreased canonical Wnt/β-catenin signaling but increased the activity of Wnt/Ca2+signaling,and DVL3 p.R222 Q only decreased the activity of Wnt/Ca2+*** also found that only the DVL2 p.R633 W mutant displayed more severe teratogenicity in zebrafish embryos than wild-type *** study demonstrates that these four rare DVL mutations,especially DVL2 p.R633 W,may contribute to human neural diseases such as NTDs and DWM by obstructing Wnt signaling pathways.

关键词： DVL genes Mutation NTD Dandy-Walker malformation Wnt pathway