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A de novo missense mutation in MPP2 confers an increased risk of Vogt–Koyanagi–Harada disease as shown by trio-based whole-exome sequencing

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Cellular & Molecular Immunology 2023年第11期20卷 1379-1392页

作者： Xianyang Liu Jiayu Meng Xingyun Liao Yusen Liu Qian Zhou Zongren Xu Shuming Yin Qingfeng Cao Guannan Su Siyuan He Wanqian Li Xiaotang Wang Guoqing Wang Dali Li Peizeng Yang Shengping Hou The First Affiliated Hospital of Chongqing Medical University ChongqingChina Chongqing Key Laboratory of Ophthalmology ChongqingChina Chongqing Eye Institute ChongqingChina Sichuan Provincial Key Laboratory for Human Disease Gene Study Sichuan Provincial People’s HospitalUniversity of Electronic Science and Technology of ChinaChengdu611731China Department of Medical Oncology Chongqing University Cancer HospitalChongqing400030China Shanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory BiologySchool of Life SciencesEast China Normal UniversityShanghai200241China Beijing Institute of Ophthalmology Beijing Tongren Eye CenterBeijing Tongren HospitalCapital Medical UniversityBeijing Ophthalmology&Visual Sciences Key LaboratoryBeijing100730China

Vogt–Koyanagi–Harada(VKH)disease is a leading cause of blindness in young and middle-aged people.However,the etiology of VKH disease remains unclear.Here,we performed the first trio-based whole-exome sequencing study,which enrolled 25 VKH patients and 50 controls,followed by a study of 2081 VKH patients from a Han Chinese population to uncover detrimental mutations.A total of 15 de novo mutations in VKH patients were identified,with one of the most important being the membrane palmitoylated protein 2(MPP2)p.K315N(MPP2-N315)mutation.The MPP2-N315 mutation was highly deleterious according to bioinformatic predictions.Additionally,this mutation appears rare,being absent from the 1000 Genome Project and Genome Aggregation Database,and it is highly conserved in 10 species,including humans and mice.Subsequent studies showed that pathological phenotypes and retinal vascular leakage were aggravated in MPP2-N315 mutation knock-in or MPP2-N315 adeno-associated virus-treated mice with experimental autoimmune uveitis(EAU).In vitro,we used clustered regularly interspaced short palindromic repeats(CRISPR‒Cas9)gene editing technology to delete intrinsic MPP2 before overexpressing wild-type MPP2 or MPP2-N315.Levels of cytokines,such as IL-1β,IL-17E,and vascular endothelial growth factor A,were increased,and barrier function was destroyed in the MPP2-N315 mutant ARPE19 cells.Mechanistically,the MPP2-N315 mutation had a stronger ability to directly bind to ANXA2 than MPP2-K315,as shown by LC‒MS/MS and Co-IP,and resulted in activation of the ERK3/IL-17E pathway.Overall,our results demonstrated that the MPP2-K315N mutation may increase susceptibility to VKH disease.

关键词： Vogt-Koyanagi-Harada disease whole exome sequencing De novo mutation Membrane palmitoylated protein 2 Annexin A2 ERK3/IL-17E pathway

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whole exome sequencing and trio analysis to broaden the variant spectrum of genes in idiopathic hypogonadotropic hypogonadism

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Asian Journal of Andrology 2021年第3期23卷 288-293页

作者： Jian Zhang Shu-Yan Tang Xiao-Bin Zhu Peng Li Jian-Qi Lu Jiang-Shan Cong Ling-Bo Wang Feng Zhang Zheng Li Obstetrics and Gynecology Hospital NHC Key Laboratory of Reproduction Regulation(Shanghai Institute of Planned Parenthood Research)School of Life SciencesFudan UniversityShanghai 200011China Department of Andrology Center for Men's HealthUrologic Medical CenterShanghai General HospitalShanghai Jiao Tong UniversityShanghai 200080China Department of Research Institute ReprcxJuction Medical CenterThe First Hospital of Lanzhou UniversityLanzhou 730000China

Dozens of genes are associated with idiopathic hypogonadotropic hypogonadism(IHH)and an oligogenic etiology has been suggested.However,the associated genes may account for only approximately 50%cases.In addition,a genomic systematic pedigree analysis is still lacking.Here,we conducted whole exome sequencing(WES)on 18 unrelated men affected by IHH and their corresponding parents.Notably,one reported and 10 novel variants in eight known IHH causative genes(AXL,CCDC141,CHD7,DMXL2,FGFR1,PNPLA6,POLR3A,and PR0KR2),nine variants in nine recently reported candidate genes(DCAF17,DCC,EGF,IGSF10,NOTCH1,PDE3A,RELN,SLIT2,and TRAPPC9),and four variants in four novel candidate genes for IHH(CCDC88C,CDON,GADL1,and SPRED3)were identified in 77.8%(14/18)of IHH cases.Among them,eight(8/18,44.4%)cases carried more than one variant in IHH-related genes,supporting the oligogenic model.Interestingly,we found that those variants tended to be maternally inherited(maternal with n=17 vs paternal with n=7;P=0.028).Our further retrospective investigation of published reports replicated the maternal bias(maternal with n=46 i^s paternal with n=28;P=0.024).Our study extended a variant spectrum for IHH and provided the first evidence that women are probably more tolerant to variants of IHH-related genes than men.

关键词： idiopathic hypogonadotropic hypogonadism maternal inheritance oligogenic inheritance whole exome sequencing

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Assessment of circulating tumor DNA in cerebrospinal fluid by whole exome sequencing to detect genomic alterations of glioblastoma

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Chinese Medical Journal 2020年第12期133卷 1415-1421页

作者： Hao Duan Ji-Long Hu Zheng-He Chen Jue-Hui Li Zhen-Qiang He Zhen-Ning Wang Guan-Hua Zhang Xiao-Yu Guo Lun Liang Yong-Gao Mou Department of Neurosurgery/Neuro-Oncology State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhouGuangdong 510060China Department of Abdominal Surgery Oncology Jiangxi Cancer HospitalNanchangJiangxi 330029China

Background:Cerebrospinal fluid(CSF)has been demonstrated as a better source of circulating tumor DNA(ctDNA)than plasma for brain tumors.However,it is unclear whether whole exome sequencing(WES)is qualified for detection of ctDNA in CSF.The aim of this study was to determine if assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma.Methods:CSFs of ten glioblastoma patients were collected pre-operatively at the Department of Neurosurgery,Sun Yat-sen University Cancer Center.ctDNA in CSF and genome DNA in the resected tumor were extracted and subjected to WES.The identified glioblastoma-associated mutations from ctDNA in CSF and genome DNA in the resected tumor were compared.Results:Due to the ctDNA in CSF was unqualified for exome sequencing for one patient,nine patients were included into the final analysis.More glioblastoma-associated mutations tended to be detected in CSF compared with the corresponding tumor tissue samples(3.56±0.75 vs.2.22±0.32,P=0.097),while the statistical significance was limited by the small sample size.The average mutation frequencies were similar in CSF and tumor tissue samples(74.1%±6.0%vs.73.8%±6.0%,P=0.924).The R132H mutation of isocitrate dehydrogenase 1 and the G34V mutation of H3 histone,family 3A(H3F3A)which had been reported in the pathological diagnoses were also detected from ctDNA in CSF by WES.Patients who received temozolomide chemotherapy previously or those whose tumor involved subventricular zone tended to harbor more mutations in their CSF.Conclusion:Assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma,which may provide useful information for the decision of treatment strategy.

关键词： Circulating tumor DNA Cerebrospinal fluid Glioblastoma Mutation whole exome sequencing

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whole exome sequencing identifies mutations of multiple genes in a Chinese cohort of 95 sporadic probands with presumptive retinitis pigmentosa

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Journal of Bio-X Research 2018年第3期1卷 132-139页

作者： Lulin Huang Jialiang Yang Shiyao Xu Yao Mao Dean Yao Lee Jiyun Yang Chao Qu Yang Li Zhenglin Yang The Key Laboratory for Human Disease Gene Study Chengdu Institute of Biology Sichuan Translational Medicine Research Hospital Chinese Academy of SciencesChengduSichuan Province Department of Ophthalmology Sichuan Academy of Medical Science and Sichuan Provincial People’s HospitalSchool of MedicineUniversity of Electronic Science and Technology of China Beijing Institute of Ophthalmology Beijing Tongren Eye CenterBeijing Tongren HospitalCapital Medical UniversityBeijing Ophthalmology&Visual Sciences Key LaboratoryBeijingChina

Retinitis pigmentosa(RP),a major cause of inherited blindness worldwide,is highly heterogeneous.This study aimed to identify mutations in a Chinese cohort of sporadic probands with presumptive RP.whole exome sequencing represents a considerable advancement in the identification of mutations associated with Mendelian diseases,such as RP.In this study,whole exome sequencing analysis was performed in a Chinese cohort of 95 sporadic probands who were initially diagnosed with RP,in order to identify disease mutations.All detected variations were confirmed by direct Sanger sequencing,and potential pathogenicity was assessed by predictions of the mutations’functions.The overall mutation rate of presumptive RP genes for this cohort was 30.5%(n=29 of 95 probands).Forty-four mutations were identified in 19 RP genes,among which 40 mutations were novel.Eleven probands carried mutations in autosomal dominant genes(38.0%),16 probands carried mutations in autosomal recessive genes(55.2%),and 2 probands carried mutations in X-linked genes(6.9%).Twenty-eight mutations in 18 genes linked to other retinal diseases in 23 probands were also identified.Overall,mutations were detected in 52 probands(54.7%).The recurrent and novel mutations reported here will expand potential understanding of the pathogenesis of RP and other retinal diseases.

关键词： gene mutation mutation proband retinitis pigmentosa whole exome sequencing

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Failure to Identify Somatic Mutations in Monozygotic Twins Discordant for Schizophrenia by whole exome sequencing

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Chinese Medical Journal 2016年第6期129卷 690-695页

作者： Nan Lyu Li-Li Guan Hong Ma Xi-Jin Wang Bao-Ming Wu Fan-Hong Shang Dan Wang Hong Wen Xin Yu Peking University Sixth Hospital Peking University Institute of Mental Health Key Laboratory of Mental Health Ministry of Health (Peking University) Beijing 100191 China The First Psychiatric Hospital of-Harbin Harbin Heilongjiang 150056 China The Mental Health Centre of Sichuan Province Mianyang Sichuan 621000 China

Background： Schizophrenia （SCZ） is a severe, debilitating, and complex psychiatric disorder with multiple causative factors. An increasing number of studies have determined that rare variations play an important role in its etiology. A somatic mutation is a rare form of genetic variation that occurs at an early stage of embryonic development and is thought to contribute substantially to the development of SCZ. The aim of the study was to explore the novel pathogenic somatic single nucleotide variations （SNVs） and somatic insertions and deletions （indels） of SCZ. Methods： One Chinese family with a monozygotic （MZ） twin pair discordant for SCZ was included. whole exome sequencing was performed in the co-twin and their parents. Rigorous filtering processes were conducted to prioritize pathogenic somatic variations, and all identified SNVs and indels were further confirmed by Sanger sequencing. Results： One somatic SNV and two somatic indels were identified after rigorous selection processes. However, none was validated by Sanger sequencing. Conclusions： This study is not alone in the failure to identify pathogenic somatic variations in MZ twins, suggesting that exonic somatic variations are extremely rare. Further efforts are warranted to explore the potential genetic mechanism of SCZ.

关键词： Monozygotic Twins Schizophrenia Somatic Mutation whole exome sequencing

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Apert syndrome diagnosed by prenatal ultrasound combined with magnetic resonance imaging and whole exome sequencing:A case report

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World Journal of Clinical Cases 2021年第4期9卷 912-918页

作者： Lei Chen Fei-Xiang Huang Ultrasonography Department Hangzhou Women’s HospitalHangzhou 310008Zhejiang ProvinceChina Department of Traditional Chinese Medicine Hangzhou Women’s HospitalHangzhou 310008Zhejiang ProvinceChina

BACKGROUND Most cases of Apert syndrome(AS)are found after birth.Cases of AS diagnosed by ultrasound combined with magnetic resonance imaging(MRI)and whole exome sequencing(WES)during pregnancy are rare.CASE SUMMARY We present the case of a 34-year old female patient(gravida 2,para 1)whose fetus was diagnosed with AS during pregnancy.Fetal ultrasound performed at 30,2/7 wk of pregnancy showed abnormalities.MRI and three-dimensional ultrasound performed at 31,1/7 wk of pregnancy showed the possibility of AS.Chromosome examination and core family WES were conducted at 31,5/7 wk of pregnancy.The results showed that FGFR2 in the fetus had a c.755C>G missense mutation in its nucleotide,and AS was confirmed.CONCLUSION This case highlights the importance of imaging examinations.Prenatal ultrasound combined with MRI can identify fetal morphological abnormalities accurately,which can be confirmed by WES.

关键词： Apert syndrome Prenatal ultrasound Magnetic resonance imaging whole exome sequencing FGFR2 Case report

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Identification of rare paired box 3 variant in strabismus by whole exome sequencing

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International Journal of Ophthalmology(English edition) 2017年第8期10卷 1223-1228页

作者： Hui-Min Gong Jing Wang Jing Xu Zhan- Yu Zhou Jing- Wen Li Shu-Fang Chen Ophthalmologic Center Qingdao Municipal Hospital theAffiliated Municipal Hospital of Qingdao University Qingdao266000 Shandong Province China Department of Ophthalmology Dezhou People's HospitalDezhou 253000 Shandong Province China Department of Ophthalmology Weifang People's HospitalWeifang 261041 Shandong Province China Department of Medical Equipment Weifang People's Hospital Weifang 261041 Shandong Province China

AIM： To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. METHODS： A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were sequenced using the next-generation sequencing technology. The resulting variants from exome sequencing were filtered by subsequent bioinformatics methods and the candidate mutation was verified as heterozygous in the affected proposita and her mother by sanger sequencing. RESULTS： whole exome sequencing and filtering identified a nonsynonymous mutation Co434G-T transition in paired box 3 （PAX3） in the two affected individuals, which were predicted to be deleterious by more than 4 bioinformatics programs. This altered amino acid residue was located in the conserved PAX domain of PAX3. This gene encodes a member of the PAX family of transcription factors, which play critical roles during fetal development. Mutations in PAX3 were associated with Waardenburg syndrome with strabismus. CONCLUSION： Our results report that the c.434G-T mutation （p.R145L） in PAX3 may contribute to strabismus, expanding our understanding of the causally relevant genes for this disorder.

关键词： strabismus whole exome sequencing paired box 3

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Genomic characterization of peritoneal lavage cytology-positive gastric cancer

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Chinese Journal of Cancer Research 2024年第1期36卷 66-77页

作者： Zhouqiao Wu Tingfei Gu Changxian Xiong Jinyao Shi Jingpu Wang Ting Guo Xiaofang Xing Fei Pang Ning He Rulin Miao Fei Shan Yuan Zhou Ziyu Li Jiafu Ji Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Gastrointestinal Cancer CenterPeking University Cancer Hospital&InstituteBeijing 100142China Department of Biomedical Informatics Department of Physiology and PathophysiologyCenter for Noncoding RNA MedicineMOE Key Lab of Cardiovascular SciencesSchool of Basic Medical SciencesPeking UniversityBeijing 100191China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchGastrointestinal Cancer CenterPeking University Cancer Hospital&InstituteBeijing 100142China

Objective: Positive peritoneal lavege cytology(CY1) gastric cancer is featured by dismal prognosis, with high risks of peritoneal metastasis. However, there is a lack of evidence on pathogenic mechanism and signature of CY1and there is a continuous debate on CY1 therapy. Therefore, exploring the mechanism of CY1 is crucial for treatment strategies and targets for CY1 gastric cancer.Methods: In order to figure out specific driver genes and marker genes of CY1 gastric cancer, and ultimately offer clues for potential marker and risk assessment of CY1, 17 cytology-positive gastric cancer patients and 31matched cytology-negative gastric cancer patients were enrolled in this study. The enrollment criteria were based on the results of diagnostic laparoscopy staging and cytology inspection of exfoliated cells. whole exome sequencing was then performed on tumor samples to evaluate genomic characterization of cytology-positive gastric cancer.Results: Least absolute shrinkage and selection operator(LASSO) algorithm identified 43 cytology-positive marker genes, while Mut Sig CV identified 42 cytology-positive specific driver genes. CD3G and CDKL2 were both driver and marker genes of CY1. Regarding mutational signatures, driver gene mutation and tumor subclone architecture, no significant differences were observed between CY1 and negative peritoneal lavege cytology(CY0).Conclusions: There might not be distinct differences between CY1 and CY0, and CY1 might represent the progression of CY0 gastric cancer rather than constituting an independent subtype. This genomic analysis will thus provide key molecular insights into CY1, which may have a direct effect on treatment recommendations for CY1and CY0 patients, and provides opportunities for genome-guided clinical trials and drug development.

关键词： Cytology gastric carcinoma peritoneal metastasis whole exome sequencing

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whole exome sequencing of multiple meningioma of different histopathological types revealed distinctive somatic mutation burden and independent clonal origins

Whole exome sequencing of multiple meningioma of different h...

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第十四届中国医师协会神经外科医师年会

作者：盛汉松林坚张弩卢相琦温州医科大学附属第二医院神经外科

Purpose Developed from neoplastic transformation of arachnoid cap cells, meningiomas are common intracranial tumors. Multiple meningiomas（MMs） are rare entities in patients without neurofibromatosis type 2. Previous studies suggest most sporadic MMs are of monoclone in origin. Methods In current study, two sporadic meningiomas, located at the right frontal and right parietal region respectively, were surgically removed from a 52-year-old male and were diagnosed as meningiothelial meningioma and fibrous meningioma（WHO grade I）. whole exome sequencing was performed on the two meningiomas and, with the patient’s peripheral lymphocyte DNA as the control, DNA from the two tumors’ exhibited distinctive somatic mutation patterns. Specifically, the meningiothelial subtype carried more single nucleotide variant（SNV） while the fibrous subtype had much higher copy number variation（CNV） burden. Besides, the two tumors demonstrated different mutation profiles in predisposing genes and known driver mutations. Results Meningiothelial subtype had missense mutations in TRAF7 and KLF4, while the fibrous subtype had frameshift deletion of NF2 gene in addition to copy number loss of NF2 and SMARCB1. These unique genetic events have been shown to be involved in the development of meningiomas. Finally, significantly mutated genes（SMGs） analysis revealed mutations of LOC729159 in the meningiothelial subtype and RPGRIP1 L and DPP6 in the fibrous subtype. Conclusions Our data suggest the two meningiomas in this patient might develop independently and the next-generation sequencing（NGS） platform is a valuable supplement to conventional pathological diagnosis. Further study is needed to ascertain whether these novel genetic events are tumorigenic or simply passenger mutations, as well as their clinical implications.

关键词： Multiple meningioma whole exome sequencing meningiothelial meningioma fibrous meningioma TRAF7 NF2 SMARCB1

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whole exome sequencing implicates PTCH1 and COL17A1 genes in ossification of the posterior longitudinal ligament of the cervical spine in Chinese patients

Whole exome sequencing implicates PTCH1 and COL17A1 genes in...

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2015中国遗传学会大会

作者： Wei Wei Hailong He ChunyueChen Yan Zhao Huling Jiang Wenting Liu Zhenfang Du Xiaoling Chen Shiyuan Shi XianningZhang Department of Biology Ningbo College of Health Sciences Department of Cell Biology and Medical Genetics Research Center of Molecular MedicineNational Education Base for Basic Medical SciencesInstitute of Cell BiologyZhejiang University School of Medicine Key Laboratory of Reproductive Genetics(Zhejiang) Ministry of Educationand Centre of Reproductive MedicineWomen's HospitalZhejiang University School of Medicine

Ossification of the posterior longitudinal ligament(OPLL;OMIM#602475)is characterized by pathological ectopic ossification of the cervical and thoracic spine ligament,leading to myeloradiculopathy as a result of chronic pressure on the spinal cord and nerve roots.OPLL was first described in detail by Tsukimoto and colleagues in 1960,and has a reported prevalence of 1.9-4.3%in the Japanese population.OPLL in Taiwan Chinese has been reported to occur at 2.8%,based on a review of hospital cervical spine radiographs.Despite a long-standing predominance in Japan,this disease has also been recognized in other geographic regions and ethnicities,although its prevalence in the US and Europe is only 0.01-1.7%.The incidence increases with age,with most cases occurring after age 40.In both males and females,the average age at onset is approximately 50years,and the reported male:female ratio is roughly 2:1.OPLL of the cervical spine can be subdivided radiograpbically into 4 types,based on the location of the spinal lesion in lateral plane radiographs:continuous,mixed,segmental,and unclassified or localized.Early clinical and epidemiological studies conducted in Japan suggested that the un-derlying cause of OPLL is multifactorial in nature,reflecting the interplay of numerous genetic and environmental factors.Genetic studies of OPLL have revealed several gene loci that may be involved in the pathogenesis of this disease.exome capture combined with massively parallel DNA sequencing has been proposed as an efficient strategy to search for disease-causing genes of both monogenic and multigenic disorders.Thus,the aim of this study was to dientify the potential susceptible genes of OPLL.We performed next-generation sequencing(WES)on two unrelated OPLL patients,coupling the Agilent whole-exome capture system to the Illumina HiSeq 2000 DNA sequencing platform,to attempt the identification of pathogenic genes for OPLL.The entire DNA coding region of the candidate genes was amplified by PCR and Sanger sequenced in 28 unrelated Han Chin

关键词： Ossification of the posterior longitudinal ligament whole exome sequencing Susceptible gene PTCH1 COL17A1

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