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Mechanism of Cu entry into the brain:many unanswered questions

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Neural Regeneration Research 2024年第11期19卷 2421-2429页

作者： Shubhrajit Roy Svetlana Lutsenko Department of Physiology Johns Hopkins University School of MedicineBaltimoreMDUSA

brain tissue requires high amounts of copper(Cu)for its key physiological processes,such as energy production,neurotransmitter synthesis,maturation of neuropeptides,myelination,synaptic plasticity,and radical scavenging.The requirements for Cu in the brain vary depending on specific brain regions,cell types,organism age,and nutritional status.Cu imbalances cause or contribute to several life-threatening neurologic disorders including Menkes disease,Wilson disease,Alzheimer’s disease,Parkinson’s disease,and others.Despite the well-established role of Cu homeostasis in brain development and function,the mechanisms that govern Cu delivery to the brain are not well defined.This review summarizes available information on Cu transfer through the brain barriers and discusses issues that require further research.

关键词： ATOX1 atp7A atp7b blood-brain barrier brain choroid plexus copper SLC31A1

Novel mutations of the atp7b gene in Han Chinese families with pre-symptomatic Wilson's disease

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World Journal of Pediatrics 2015年第3期11卷 255-260页

作者： Zhe-Feng Yuan Wei Wu Yong-Lin Yu Jue Shen Shan-Shan Mao Feng Gao Zhe-Zhi Xia Department of Neurology Children's HospitalZhejiang University School of MedicineHangzhou 310003China Department of Endocrinology Children's HospitalZhejiang University School of MedicineHangzhou 310003China

background:Wilson's disease(WD)is an autosomal recessive genetic disorder of copper metabolism,caused by mutations in the atp7b gene,resulting in copper accumulation in the liver,brain,kidney,and cornea and leading to significant disability or death if untreated.Early diagnosis and proper therapy usually predict a good prognosis,especially in pre-symptomatic WD.Genetic testing is the most accurate and effective diagnostic method for early diagnosis.Methods:The clinical and biochemical features of three unrelated Han Chinese families with pre-symptomatic WD were reported.The molecular defects in these families were investigated by polymerase chain reaction and DNA sequencing.Hundred healthy children with the same ethnic background served as controls.bioinformatic tools(polymorphism phenotyping-2,sorting intolerant from tolerant,protein analysis through evolutionary relationships,and predictor of human deleterious single nucleotide polymorphisms)were combined and used to predict the functional effects of mutations.Results:We identified 2 novel atp7b mutations(p.Leu692Pro and p.Asn728Ser)and 3 known mutations(p.Met769fs,p.Arg778Leu and p.Vall216Met)in these Chinese WD families.These mutations were not observed in the 100 normal controls.The bioinformatic method showed that p.Leu692Pro and p.Asn728Ser mutations are pathogenic.Conclusions:Our research enriches the mutation spectrum of the atp7b gene worldwide and provides valuable information for studying the mutation types and mode of inheritance of atp7b in the Chinese population.Liver function analysis and genetic testing in young children with WD are necessary to shorten the time to the initiation of therapy,reduce damage to the liver and brain,and improve prognosis.

关键词： atp7b Chinese mutation Wilson's disease

Identification of two novel mutations in the atp7b gene that cause Wilson's disease

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World Journal of Pediatrics 2017年第4期13卷 387-391页

作者： Hong-Wen Zhu Zhong-bin Tao Gang Su Qiao-Ying Jin Liang-Tao Zhao Jia-Rui Zhu Jun Yan Tian-Yu Yu Jie-Xian Ding Yu-Min Li Laboratory of Medical Genetics The Second Hospital of Lanzhou UniversityLanzhouChina Key Laboratory of Digestive System Tumors of Gansu Province LanzhouChina Department of Pediatrics The First Hospital of Lanzhou UniversityLanzhouChina Institute of Genetics Lanzhou University School of Basic Medical Sciences Second Clinical Medical College of Lanzhou University

background:Wilson's disease is an autosomal recessive disorder characterized by liver disease and/or neurologic deficits due to copper accumulation and is caused by pathogenic mutations in the atp7b gene.Methods:Two unrelated Chinese patients born to nonconsanguineous parents who were diagnosed with earlyonset Wiison's disease.DNA sequencing and bioinformation analysis were conducted.Results:We have identified four mutations in two family trios,of which two were novel,namely,c.3028A>G(p.K1010E) and c3992T>G (p.Y1331X),in each patient.Conclusions:Gene testing is playing an important role in diagnosis of Wilson's disease.The early-onset of Wilson's disease is apparently not associated with P-atpase domain in the atp7b protein.Our findings further widen the spectrum of mutations involving the atp7b gene.

关键词： atp7b mutation sequencing Wilson's disease

Functional analysis and drug response to zinc and D-penicillamine in stable atp7b mutant hepatic cell lines

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World Journal of Gastroenterology 2016年第16期22卷 4109-4119页

作者： Gursimran Chandhok Judit Horvath Annu Aggarwal Mohit bhatt Andree Zibert Hartmut HJ Schmidt Klinik fur Transplantationsmedizin Universitatsklinikum Munster D-48149 Munster Germany Institut fur Humangenetik Westfalische Wilhelms-Universitat D-48149 Munster Germany Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute Mumbai 400103 India

AIM: To study the effect of anti-copper treatment for survival of hepatic cells expressing different atp7 b mutations in cell culture. METHODS: The most common Wilson disease(WD) mutations p.H1069 Q, p.R778 L and p.C271*, found in the atp7 b gene encoding a liver copper transporter, were studied. The mutations represent major genotypes of the United States and Europe, China, and India, respectively. A human hepatoma cell line previously established to carry a knockout of atp7 b was used to stably express WD mutants. m RNA and protein expression of mutant atp7 b, survival of cells, apoptosis, and protein trafficking were determined.RESULTS: Low temperature increased atp7 b protein expression in several mutants. Intracellular atp7 b localization was significantly impaired in the mutants. Mutants were classified as high, moderate, and no survival based on their viability on exposure to toxic copper. Survival of mutant p.H1069 Q and to a lesser extent p.C271* improved by D-penicillamine(DPA) treatment, while mutant p.R778 L showed a pronounced response to zinc(Zn) treatment. Overall, DPA treatment resulted in higher cell survival as compared to Zn treatment; however, only combined Zn + DPA treatment fully restored cell viability. CONCLUSION: The data indicate that the basic impact of a genotype might be characterized by analysis of mutant hepatic cell lines.

关键词： atp7b D-penicillamine Zinc Mutations Wilson disease Therapy

靶向小鼠atp7b基因的CRISPR/Cas9系统构建与评价

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现代医药卫生 2022年第11期38卷 1801-1805,1811页

作者：李欣怡孙雪梅付灿岳鹏鹏于鸿浩李勇桂林医学院生物技术学院广西桂林541199

目的使用CRISPR/Cas9系统靶向小鼠atp7b基因,建立高效的atp7b基因CRISPR/Cas9编辑系统,模拟人atp7b基因突变,为更深入地开展威尔逊病(WD)分子机制研究和疾病干预奠定基础。方法选择我国WD的热点突变,对应小鼠atp7b基因上的突变区域,设... 详细信息

目的使用CRISPR/Cas9系统靶向小鼠atp7b基因,建立高效的atp7b基因CRISPR/Cas9编辑系统,模拟人atp7b基因突变,为更深入地开展威尔逊病(WD)分子机制研究和疾病干预奠定基础。方法选择我国WD的热点突变,对应小鼠atp7b基因上的突变区域,设计单向导RNA(sgRNA),构建表达质粒,并与Cas9表达质粒共转染到小鼠N2a细胞,采用药物(嘌呤霉素和杀稻瘟菌素)筛选阳性细胞并提取gDNA,将目标位点的DNA片段进行聚合酶链式反应(PCR)扩增,然后通过TA克隆序列结果分析对目标基因的打靶效率。结果成功设计sgRNAs序列,并使用CRISPR/Cas9系统编辑了小鼠atp7b基因,编辑效率为53.85%,创建了atp7b基因突变细胞模型。结论通过靶向小鼠atp7b基因,成功构建CRISPR/Cas9系统,这对深入研究WD的致病机制、探讨WD的治疗具有重要意义。

关键词：基因编辑 CRISPR/Cas9 单向导RNA atp7b 威尔逊病

基于转录组测序探究atp7b基因缺陷小鼠铜累积诱导肝细胞自噬的相关机制

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中国生物工程杂志 2021年第9期41卷 10-19页

作者：李潇瑾李艳萌李振坤徐安健杨晓曦黄坚首都医科大学附属北京友谊医院科研实验中心北京市临床医学研究所北京100050

目的:分析atp7b基因缺陷(Wilson’s disease,WD)小鼠肝脏组织中自噬相关基因的表达和自噬相关蛋白的相互作用方式,探讨铜累积诱导肝内自噬活化的可能机制。方法:对4周龄和12周龄WD小鼠肝组织进行铜含量检测和转录组测序,对差异基因进行G... 详细信息

目的:分析atp7b基因缺陷(Wilson’s disease,WD)小鼠肝脏组织中自噬相关基因的表达和自噬相关蛋白的相互作用方式,探讨铜累积诱导肝内自噬活化的可能机制。方法:对4周龄和12周龄WD小鼠肝组织进行铜含量检测和转录组测序,对差异基因进行GO和KEGG富集分析,筛选自噬相关差异基因做qRT-PCR和Western blot验证,采用GeneMANIA数据库构建自噬相关差异蛋白的互作网络(PPI)并进行功能注释分析,抑制自噬相关蛋白的表达分析其对自噬的影响。结果:与野生型小鼠相比,WD小鼠肝铜含量显著升高,铜累积导致基因表达模式改变;基于GO数据库统计自噬相关差异基因数目,4周龄和12周龄分别有8个、51个,基于KEGG数据库统计,4周龄和12周龄分别有5个、19个;筛选Ulk1、Ddit4、Plk3等9个基因进行qRT-PCR,定量结果与测序结果表达趋势基本一致;其编码的蛋白质通过共表达、共定位等方式互相作用;Western blot结果显示铜累积导致Ulk1、Plk3、Park2蛋白表达显著增加和细胞自噬发生,抑制Ulk1、Plk3、Park2的蛋白质表达可显著下调细胞自噬水平。结论:WD不同阶段的铜累积可调节肝脏多个自噬相关基因的表达,通过其编码的自噬相关蛋白的互相作用共同诱导肝脏自噬活化以缓解肝损伤。

关键词： atp7b 威尔逊病肝豆状核变性铜累积自噬

累代遗传的肝豆状核变性的临床与基因诊断分析

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中风与神经疾病杂志 2024年第1期41卷 52-57页

作者：刘力生方明娟年娜赵雯童广安王佳炜胡文彬安徽中医药大学神经病学研究所安徽合肥230061 安徽中医药大学神经病学研究所附属医院神经内科安徽合肥230061

目的总结分析累代遗传的肝豆状核变性(HLD)的临床与基因诊断思路。方法通过对2017年6月—2023年7月我科收治的3例HLD患者的现病史、既往史、家族史的收集调查,并对其可能患病的一级亲属进行肝功能、血清铜蓝蛋白(CP)、基础24 h尿铜(尿Cu... 详细信息

目的总结分析累代遗传的肝豆状核变性(HLD)的临床与基因诊断思路。方法通过对2017年6月—2023年7月我科收治的3例HLD患者的现病史、既往史、家族史的收集调查,并对其可能患病的一级亲属进行肝功能、血清铜蓝蛋白(CP)、基础24 h尿铜(尿Cu)、角膜K-F环(KFR)、腹部彩超及atp7b基因检测、分析。结果3个家系的先证者的父母或子女中共有2例转氨酶升高,3例CP减低和尿Cu升高,1例患有脂肪肝,atp7b基因均为复合杂合突变,KFR均阴性。明确了3个累代遗传的HLD家系,并发现了一个新的致病突变。结论单纯以CP、KFR或腹部彩超等筛查症状前期HLD存在较大局限性,尿Cu检测敏感性良好,基因检测可进一步提高诊断的准确性。由于HLD人群携带率较高,HLD的累代遗传现象值得重视。

关键词：肝豆状核变性累代遗传 atp7b 诊断分析

75例儿童肝豆状核变性的临床及基因变异特征

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基础医学与临床 2024年第7期44卷 1008-1012页

作者：张思敏王伟马明圣邱正庆中国医学科学院北京协和医学院北京协和医院儿科北京100730

目的了解儿童肝豆状核变性的起病临床特点,明确基因诊断在儿童肝豆状核变性患者中的意义。方法选取2011年至2018年就诊于北京协和医院儿科门诊的75例肝豆状核变性患儿进行回顾性研究;进行铜离子转运atp酶β肽(atp7b)基因测序、多重连接... 详细信息

目的了解儿童肝豆状核变性的起病临床特点,明确基因诊断在儿童肝豆状核变性患者中的意义。方法选取2011年至2018年就诊于北京协和医院儿科门诊的75例肝豆状核变性患儿进行回顾性研究;进行铜离子转运atp酶β肽(atp7b)基因测序、多重连接探针扩增技术(MLPA)分析;对其起病时临床表现及基因检测结果进行总结。结果75例儿童肝豆状核变性患者中,男女比例为1.27∶1,年龄为(6.5±4.0)岁(1.3~17.5岁)。55例以无症状肝酶升高起病,所有患者铜蓝蛋白均72例患者24小时尿铜>40μg,其中29例患者24小时尿铜在40~100μg之间,16例患儿K-F环阳性,可以临床确诊的共有16例(21%),有15例年龄均>7岁。75例进行了atp7b基因检测,共检出48种致病变异。最常见的致病变异为c.2333G>T、p.R778L、c.2621C>L、p.A874V、c.2975C>T、p.P992L,其等位基因频率分别为30.49%、14.89%、9.92%。结论对于儿童患者,多表现为无症状肝酶升高,K-F环阳性率较低,临床确诊难度大。本研究临床确诊率为21.33%,基因检测对于该病的早期诊断和治疗具有重要意义。

关键词：肝豆状核变性临床特点儿童 atp7b

atp7b和PCNA在大鼠、小鼠空肠及肾的表达

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动物学杂志 2010年第4期45卷 156-163页

作者：王杰玉杨杰李勇莉王国栋侯锐高福莲新乡医学院基础医学院新乡453003 新乡医学院组胚教研室新乡453003

随机选取6只SD大鼠(Rattus norvegicus)和7只昆明小鼠(Mus musculus),用免疫组织化学单标和双标法检测其空肠及肾atp7b与PCNA的表达,并分析表达的相关性。结果发现,对于大鼠及小鼠,atp7b主要表达于小肠腺与空肠上皮的纹状缘、近腔面和... 详细信息

随机选取6只SD大鼠(Rattus norvegicus)和7只昆明小鼠(Mus musculus),用免疫组织化学单标和双标法检测其空肠及肾atp7b与PCNA的表达,并分析表达的相关性。结果发现,对于大鼠及小鼠,atp7b主要表达于小肠腺与空肠上皮的纹状缘、近腔面和近基底部,肾小管与集合管;PCNA在空肠腺及小肠绒毛中轴的结缔组织中表达,在肾小管、集合管及肾小球的少数细胞表达;atp7b与PCNA虽在空肠上皮、肠腺、肾小管和集合管有共表达现象,但二者在大鼠与小鼠空肠及肾的免疫反应阳性物积分光密度间均无显著相关性(P>0.05)。提示atp7b与PCNA在正常大鼠与小鼠空肠及肾的表达相似,atp7b的表达与组织增殖活跃程度间的相关性不明显。

关键词： atp7b PCNA 空肠肾免疫组织化学法