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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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A novel De novo mutation of the Nipped-B-like gene in an isolated Chinese patient with Cornelia de Lange syndrome

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Chinese Medical Journal 2013年第1期126卷 191-192页

作者： XU Wei-zhen CHEN Chun-yue CHEN Xiao-ling ZHAO Yan LIU Wen-ting DU Zhen-fang ZHANG Xian-ning Institute of Cancer Zhejiang Cancer Hospital Hangzhou Zhejiang310022 China department of Cell Biology and Medical Genetics NationalEducation Base for Basic Medical Sciences Institute of CellBiology Zhejiang University School of Medicine HangzhouZhejiang 310058 China department of Reproductive Medicine Hangzhou Red CrossHospital Hangzhou Zhejiang 310003 China

Cornelia de Lange syndrome （CdLS; OMIM： 122470） is characterized by distinctive facial features, growthretardation, hirsutism, and upper limb reduction defects. Craniofacial features manifest as synophrys, arched eyebrows, long thick eyelashes, a small upturned nose, small widely-spaced teeth, and microcephaly. The intelligence quotient （IQ） is usually below the normal level. More phenotypes are frequently found, such as cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia.

关键词： Nipped-B-like gene Cornelia de Lange syndrome De novo mutation

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A Novel de novo GATA-binding Protein 3 mutation in a Patient with Hypoparathyroidism, Sensorineural deafness, and Renal Dysplasia Syndrome

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Chinese Medical Journal 2017年第11期130卷 1378-1380页

作者： Xue-Ying Chu Yue-Peng Li Min Nie Ou Wang Yan Jiang Mei Li Wei-Bo Xia Xiao-Ping Xing department of Endocrinology Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100730 China

INTRODUCTION Hypoparathyroidism, sensorineural deafness, and renal dysplasia （HDR） syndrome, also called Barakat syndrome, is an autosomal dominant genetic disease caused by haploinsufficiency of the GATA-binding pr... 详细信息

关键词： De novo mutation GATA-binding Protein 3 Gene Hypoparathyroidism, Sensorineural deafness, and Renal DysplasiaSyndrome

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De novo mutation of EXT1 gene occurring at early embryogenesis leads to mild hereditary multiple osteochondromas

De novo mutation of EXT1 gene occurring at early embryogenes...

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中国的遗传学研究——遗传学进步推动中国西部经济与社会发...

作者：廖娟王志红周春燕郭小燕兰风华南京军区福州总医院临床遗传与实验医学科

We identified a gonosomal mosaic with a mutation in EXT1,1474475 del TC,occurring de novo in early embryogenesis.This De novo mutation resulted in only a fraction of cells(including chondrocytes) in the body being mutants of EXT1,and in turn led to mild osteochondromas.Our finding supports a two-hit model in osteochondromagenesis and illustrates that De novo mutation may be a factor that influences intra-familial and inter-familal variability of osteochondromas.

关键词： De novo mutation multiple osteochondroma gonosomal mosaic embryogenesis

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Insights into the genetic architecture of congenital heart disease from animal modeling

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Zoological Research 2023年第3期44卷 577-590页

作者： Wenjuan Zhu Cecilia W.Lo The Chinese University of Hong Kong Hong Kong SARChina department of developmental Biology University of Pittsburgh School of MedicinePittsburghPA15201 USA Kunming Institute of Zoology-The Chinese University of Hong Kong(KIZ-CUHK)Joint Laboratory of Bioresources and Molecular Research of Common Diseases Hong Kong SARChina

Congenital heart disease(CHD)is observed in up to 1%of live births and is one of the leading causes of mortality from birth defects.While hundreds of genes have been implicated in the genetic etiology of CHD,their role in CHD pathogenesis is still poorly understood.This is largely a reflection of the sporadic nature of CHD,as well as its variable expressivity and incomplete penetrance.We reviewed the monogenic causes and evidence for oligogenic etiology of CHD,as well as the role of De novo mutations,common variants,and genetic modifiers.For further mechanistic insight,we leveraged single-cell data across species to investigate the cellular expression characteristics of genes implicated in CHD in developing human and mouse embryonic hearts.Understanding the genetic etiology of CHD may enable the application of precision medicine and prenatal diagnosis,thereby facilitating early intervention to improve outcomes for patients with CHD.

关键词： Congenital heart disease Genetic modifier Single cell sequencing De novo mutation Protective variant Common copy number variant

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Reconstructing early transmission networks of SARS-CoV-2 using a genomic mutation model

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Zoological Research 2023年第3期44卷 494-504页

作者： Chao-Yuan Cheng Zhi-Bin Zhang State Key Laboratory of Integrated Management of Pest Insects and Rodents Institute of ZoologyChinese Academy of SciencesBeijing 100101China CAS Center for Excellence in Biotic Interactions University of Chinese Academy of SciencesBeijing 100049China

The coronavirus disease 2019(COVID-19)pandemic has greatly damaged human society,but the origins and early transmission patterns of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)pathogen remain unclear.Here,we reconstructed the transmission networks of SARS-CoV-2 during the first three and six months since its first report based on ancestor-offspring relationships using BANAL-52-referenced mutations.We explored the position(i.e.,root,middle,or tip)of early detected samples in the evolutionary tree of SARS-CoV-2.In total,6799 transmission chains and 1766 transmission networks were reconstructed,with chain lengths ranging from 1-9 nodes.The root node samples of the 1766 transmission networks were from 58 countries or regions and showed no common ancestor,indicating the occurrence of many independent or parallel transmissions of SARS-CoV-2 when first detected(i.e.,all samples were located at the tip position of the evolutionary tree).No root node sample was found in any sample(n=31,all from the Chinese mainland)collected in the first 15 days from 24 december 2019.Results using six-month data or RaTG13-referenced mutation data were similar.The reconstruction method was verified using a simulation approach.Our results suggest that SARS-CoV-2 may have already been spreading independently worldwide before the outbreak of COVID-19 in Wuhan,China.Thus,a comprehensive global survey of human and animal samples is essential to explore the origins of SARS-CoV-2 and its natural reservoirs and hosts.

关键词： SARS-CoV-2 Transmission chain Transmission network Ancestor-offspring relationship De novo mutation Back mutation Secondary mutation

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Recombination and mutation shape variations in the major histocompatibility complex

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Journal of Genetics and Genomics 2022年第12期49卷 1151-1161页

作者： Yuying Sun Fang Yuan Ling Wang Dongfa Dai Zhijian Zhang Fei Liang Nan Liu Juan Long Xiao Zhao Yongzhi xi department of Immunology and National Immunoassay Laboratory Fifth Medical Center of Chinese PLA General HospitalBeijing 100071China Institute of Beijing 307 Hospital Anhui Medical UniversityHefeiAnhui 230032China

The major histocompatibility complex(MHC)is closely associated with numerous diseases,but its high degree of polymorphism complicates the discovery of disease-associated variants.In principle,recombination and De novo mutations are two critical factors responsible for MHC polymorphisms.However,direct evidence for this hypothesis is lacking.Here,we report the generation of fine-scale MHC recombination and De novo mutation maps of~5 Mb by deep sequencing(>100×)of the MHC genome for 17 MHC recombination and 30 non-recombination Han Chinese families(a total of 190 individuals).Recombination hotspots and Han-specific breakpoints are located in close proximity at haplotype block boundaries.The average MHC De novo mutation rate is higher than the genome-wide De novo mutation rate,particularly in MHC recombinant individuals.Notably,mutation and recombination generated polymorphisms are located within and outside linkage disequilibrium regions of the MHC,respectively,and evolution of the MHC locus was mainly controlled by positive selection.These findings provide insights on the evolutionary causes of the MHC diversity and may facilitate the identification of disease-associated genetic variants.

关键词： Major histocompatibility complex(MHC) Recombination De novo mutation Positive selection Disease-associated genetic variants

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de novo Post-zygotic Somatic mutation of PHEX in Mosaic Fashion Cause X-linked Hypophosphatemic Rickets

de novo Post-zygotic Somatic Mutation of PHEX in Mosaic Fash...

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2014浙江省医学会医学遗传学学术年会

作者： C.Weng P.Yu M.Qi School of Medicine Zhejiang university James D Watson Institute of genome Sciences department of Pathology and Laboratory Medicine University of Rochester Medical Center

Background:X-linked hypophosphatemic rickets(XLHR),an X linked dominant disorder,is characterized mainly by renal phosphate wasting with hypophosphatemia,short stature and abnormal bone mineralization.A variety of mutations in PHEX,the only gene causing XLHR,have been identified in previous studies.But somatic mutation in XLHR was rarely documented.Method:All 22 exons and their exon-intron boundaries in the PHEX gene were screened using PCR followed by sequencing.The mutation effect was subsequently predicted via bioinformatics.TA clone assay was performed to confirm the heterozygous allele and estimate the ratio.And Real-time PCR was applied to determine the copy number of PHEX Result:A novel splice site mutation c.1769-1G>A was identified in this proband,and it probably cause frame shift and induce a premature stop codon,resulting in loss of function of PHEX.No any family history of XLHR was declared.Karyotype analysis indicates normal number and structure of chromosomes.Real-Time PCR indicates the normal copy number of PHEX,supporting the result of karyotype analysis and ruling out the possibility of mutation on extra gene copies.For this male proband,TA clone assay on DNA from peripheral blood shows the frequency of normal(G)to mutant allele(A)on X chromosome as 19:13.Conclusion:This novel mutation is de novo in mosaic fashion that may be induced during early post-zygotic period.Taking mosaic somatic mutation of PHEX into consideration is strongly suggested in genetic counseling and etiology research for XLHR.

关键词： X linked dominant disorder hypophosphatemic rickets PHEX gene De novo mutation mosaic fashion

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Integrative modeling of transmitted and de novo variants identifies novel risk genes for congenital heart disease

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Quantitative Biology 2021年第2期9卷 216-227页

作者： Mo Li Xue Zeng Chentian Jin Sheng Chih Jin Weilai Dong Martina Brueckner Richard Lifton Qiongshi Lu Hongyu Zhao department of Biostatistics Yale School of Public HealthNew HavenCT 06510USA department of Genetics Yale UniversityNew HavenCT 06510USA department of Molecular Cellular&Developmental BiologyYale UniversityCT 06510USA department of Genetics Washington University School of MedicineSt LouisMO 63110USA department of Pediatrics Yale UniversityNew HavenCT 06510USA Laboratory of Human Genetics and Genomics Rockefeller UniversityNew YorkNY 10065USA department of Biostatistics and Medical Informatics University of Wisconsin-MadisonMadisonWl 53792USA Program of Computational Biology and Bioinformatics Yale UniversityNew HavenCT 06510USA

Background:Whole-exome sequencing(WES)studies have identified multiple genes enriched for De novo mutations(DNMs)in congenital heart disease(CHD)probands.However,risk gene identification based on DNMs alone remains statistically challenging due to heterogenous etiology of CHD and low mutation rate in each gene.Methods:In this manuscript,we introduce a hierarchical Bayesian framework for gene-level association test which jointly analyzes de novo and rare transmitted variants.Through integrative modeling of multiple types of genetic variants,gene-level annotations,and reference data from large population cohorts,our method accurately characterizes the expected frequencies of both de novo and transmitted variants and shows improved statistical power compared to analyses based on DNMs only.Results:Applied to WES data of 2,645 CHD proband-parent trios,our method identified 15 significant genes,half of which are novel,leading to new insights into the genetic bases of CHD.Conclusion:These results showcase the power of integrative analysis of transmitted and de novo variants for disease gene discovery.

关键词： rare variants gene-level association test congenital heart disease De novo mutation

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Massive‐scale genomic analysis reveals SARS‐CoV‐2 mutation characteristics and evolutionary trends

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mLife 2022年第3期1卷 311-322页

作者： Yamin Sun Min Wang Wenchao Lin Wei Dong Jianguo Xu Research Institute of Public Health Nankai UniversityTianjinChina TEDA Institute of Biological Sciences and Biotechnology Nankai UniversityTianjinChina Engineering and Research Center for Microbial Functional Genomics and detection Ministry of EducationNankai UniversityTianjinChina State Key Laboratory for Infectious Disease Prevention and Control Chinese Center for Disease Control and PreventionNational Institute for Communicable Disease Control and PreventionBeijingChina Research Units of Discovery of Unknown Bacteria and Function Chinese Academy of Medical SciencesBeijingChina

The severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2)pandemic resulted in significant societal costs.Hence,an in‐depth understanding of SARS‐CoV‐2 virus mutation and its evolution will help determine the direction of the COVID‐19 pandemic.In this study,we identified 296,728 De novo mutations in more than 2,800,000 high‐quality SARS‐CoV‐2 genomes.All possible factors affecting the mutation frequency of SARS‐CoV‐2 in human hosts were analyzed,including zinc finger antiviral proteins,sequence context,amino acid change,and translation efficiency.As a result,we proposed that when adenine(A)and tyrosine(T)bases are in the context of AM(M stands for adenine or cytosine)or TA motif,A or T base has lower mutation frequency.Furthermore,we hypothesized that translation efficiency can affect the mutation frequency of the third position of the codon by the selection,which explains why SARS‐CoV‐2 prefers AT3 codons usage.In addition,we found a host‐specific asymmetric dinucleotide mutation frequency in the SARS‐CoV‐2 genome,which provides a new basis for determining the origin of the SARS‐CoV‐2.Finally,we summarize all possible factors affecting mutation frequency and provide insights into the mutation characteristics and evolutionary trends of SARS‐CoV‐2.

关键词： De novo mutation evolutionary trends mutation characteristics mutation frequency SARS‐CoV‐2

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