目的：研究北京汉族人群中ABCA4基因单核苷酸多态性,为病因学研究提供依据。方法：选取国际人类基因组单体型图计划（Hap Map）公布的北京汉族人群（Han Chinese in Beijing,China,CHB）ABCA4基因SNPs基因型数据,利用Haploview4.2软件...目的：研究北京汉族人群中ABCA4基因单核苷酸多态性,为病因学研究提供依据。方法：选取国际人类基因组单体型图计划（Hap Map）公布的北京汉族人群（Han Chinese in Beijing,China,CHB）ABCA4基因SNPs基因型数据,利用Haploview4.2软件对其进行分析。结果：Hapmap提供的343个ABCA4基因的SNPs中,有129个（37.6%）纯合基因型SNPs和214个（62.39%）合格SNPs。本研究共确定95个标签SNPs,构建了3个单体域,各单体域均以前2种单体型为主,累计频率在91.1%-94.0%之间。结论：通过分析北京汉族人群ABCA4基因SNPs数据,得到了标签SNPs、单体域和主要单体型,为进一步的病因学研究打下了基础。展开更多
AIM: To identify the disease-associated mutations in a Chinese Stargardt disease(STGD) family, extend the existing spectrum of disease-causing mutations and further define the genotype-phenotype correlations.METHODS: ...AIM: To identify the disease-associated mutations in a Chinese Stargardt disease(STGD) family, extend the existing spectrum of disease-causing mutations and further define the genotype-phenotype correlations.METHODS: A Chinese STGD family and 200 normal controls were collected. Whole exome sequencing(WES) and bioinformatics analysis were performed to find the pathogenic gene mutation. Physico-chemical parameters of mutant and wildtype proteins were computed by Prot Param tool. Domains analysis was performed by SMART online software. HOPE online software was used to analyze the structural effects of mutation. Immunofluorescence, quantitative real-time polymerase chain reaction and Western blotting were used for expression analysis.RESULTS: Using WES, a novel homozygous mutation(NM_000350: c.G3190 C, p.G1064 R) in ABCA4 gene was identified. This mutation showed co-segregation with phenotype in this family. It was not found in the 200 unrelated health controls and absent from any databases. It was considered "Deleterious" as predicted by five function prediction softwares, and was highly conserved during evolution. ABCA4 was expressed highly in the human eye and mouse retina. The p.G1064 R was located in AAA domain, may force the local backbone into an incorrect conformation, disturb the local structure, and reduce the activity of ATPase resulting in the disease pathology. CONCLUSION: We define a novel pathogenic mutation(c.G3190 C of ABCA4) of STGD. This extends the existing spectrum of disease-causing mutations and further defines the genotype-phenotype correlations.展开更多
Background: The majority of studies on the retina-specific ATP-binding casse tte transporter (ABCA4) gene have focussed on molecular genetic analysis; compar atively few studies have described the clinical aspects of ...Background: The majority of studies on the retina-specific ATP-binding casse tte transporter (ABCA4) gene have focussed on molecular genetic analysis; compar atively few studies have described the clinical aspects of ABCA4-associated ret inal disorders. In this study, we demonstrate the spectrum of retinal dystrophie s associated with ABCA4 gene mutations. Methods: Nine well-documented patients representing distinct phenotypes in the continuum of ABCA4-related disorders we re selected. All patients received an extensive ophthalmologic evaluation, inclu ding kinetic perimetry, fluorescein angiography, and electroretinography (ERG). Mutation analysis had been performed previously with the genotyping microarray ( ABCR400 chip) and/or single-strand conformation polymorphism analysis in combin ation with direct DNA sequencing. Results: In all patients, at least one patholo gic ABCA4 mutation was identified. Patient 10034 represented the mild end of the phenotypic spectrum, demonstrating exudative age-related macular degeneration (AMD). Patient 24481 received the diagnosis of late-onset fundus flavimaculatus (FFM), patient 15168 demonstrated the typical FFM phenotype, and patient 19504 had autosomal recessive Stargardt disease (STGD1). Patients 11302 and 7608 exhib ited progression from FFM/STGD1 to cone-rod dystrophy (CRD). A more typical CRD phenotype was found in patients 15680 and 12608. Finally, the most severe ABCA4 -associated phenotype was retinitis pigmentosa (RP) in patient 11366. This phen otype was characterised by extensive atrophy with almost complete loss of periph eral and central retinal functions. Conclusion: We describe nine patients during different stages of disease progression; together, these patients form a contin uum of ABCA4-associated phenotypes. Besides characteristic disorders such as FF M/STGD1, CRD and RP, intermediate phenotypes may be encountered. Moreover, as th e disease progresses, marked differences may be observed between initially compa rable phenotypes. In contrast, distinctly different phenotypes may converge to a similar final stage, characterised by extensive chorioretinal atrophy and very low visual functions. The identified ABCA4 mutations in most, but not all, patie nts were compatible with the resulting phenotypes, as predicted by the genotype -phenotype model for ABCA4-associated disorders. With the advent of therapeuti c options, recognition by the general ophthalmologist of the various retinal phe notypes associated with ABCA4 mutations is becoming increasingly important.展开更多
目的研究全基因组甲基化对心力衰竭患者心肌基因表达的影响。方法取心脏移植中供体左心室心肌标本8例作为正常对照组,行心脏移植的心力衰竭患者自身左心室心肌标本14例作为实验组,提取基因组基因通过甲基化DNA免疫共沉淀结合甲基化芯片...目的研究全基因组甲基化对心力衰竭患者心肌基因表达的影响。方法取心脏移植中供体左心室心肌标本8例作为正常对照组,行心脏移植的心力衰竭患者自身左心室心肌标本14例作为实验组,提取基因组基因通过甲基化DNA免疫共沉淀结合甲基化芯片技术(methylated DNA immunoprecipitation-chip,MeDIP-chip)及基因表达谱芯片进行高通量的快速筛选。然后,得到MeDIP-chip初筛后的2个甲基化异常基因abca4和cd200进行亚硫酸氢钠测序PCR。结果疾病组abca4基因启动子区甲基化率为85.5%,正常组基因启动子区甲基化率为91.2%;疾病组基因启动子区甲基化率比正常组基因启动子区甲基化率低5.7%,心衰组cd200基因启动子区甲基化率为50.5%,正常组基因启动子区甲基化率为57.1%。结论 abca4和cd200启动子区甲基化改变会影响自身的基因表达量。心衰时DNA启动子区甲基化会发生改变,并且DNA启动子区的甲基化会伴随着基因表达量的改变。展开更多
Background:Stargardt disease 1(STGD1;MIM 248200)is a monogenic form of autosomal recessive genetic disease caused by mutation in ABCA4.This gene has a major role in hydrolyzing N-retinylidene-phosphatidylethanolamine ...Background:Stargardt disease 1(STGD1;MIM 248200)is a monogenic form of autosomal recessive genetic disease caused by mutation in ABCA4.This gene has a major role in hydrolyzing N-retinylidene-phosphatidylethanolamine to all-trans-retinal and phosphatidylethanolamine.The purpose of this study is to identify the frequency of putative disease-causing mutations associated with Stargardt disease in a South Indian population.Methods:A total of 28 clinically diagnosed Stargardt-like phenotype patients were recruited from south India.Ophthalmic examination of all patients was carefully carried out by a retina specialist based on the stages of fundus imaging and ERG grouping.Genetic analysis of ABCA4 was performed for all patients using Sanger sequencing and clinical exome sequencing.Results:This study identified disease-causing mutations in ABCA4 in 75%(21/28)of patients,7%(2/28)exhibited benign variants and 18%(5/28)were negative for the disease-causing mutation.Conclusion:This is the first study describing the genetic association of ABCA4 disease-causing mutation in South Indian Stargardt 1 patients(STGD1).Our findings highlighted the presence of two novel missense mutations and an(in/del,single base pair deletion&splice variant)in ABCA4.However,genetic heterogeneity in ABCA4 mutants requires a larger sample size to establish a true correlation with clinical phenotype.展开更多
文摘目的：研究北京汉族人群中ABCA4基因单核苷酸多态性,为病因学研究提供依据。方法：选取国际人类基因组单体型图计划（Hap Map）公布的北京汉族人群（Han Chinese in Beijing,China,CHB）ABCA4基因SNPs基因型数据,利用Haploview4.2软件对其进行分析。结果：Hapmap提供的343个ABCA4基因的SNPs中,有129个（37.6%）纯合基因型SNPs和214个（62.39%）合格SNPs。本研究共确定95个标签SNPs,构建了3个单体域,各单体域均以前2种单体型为主,累计频率在91.1%-94.0%之间。结论：通过分析北京汉族人群ABCA4基因SNPs数据,得到了标签SNPs、单体域和主要单体型,为进一步的病因学研究打下了基础。
基金Supported by the National Natural Science Foundation of China(No.81500763,No.81800805,No.81600721)Young and Middle-aged Scientists Research Awards Fund of Shandong Province(No.BS2015YY014)+1 种基金China Postdoctoral Science Foundation(No.2019M652311)Medical and Health Science and Technology Development Project of Shandong Province(No.2017WS012)。
文摘AIM: To identify the disease-associated mutations in a Chinese Stargardt disease(STGD) family, extend the existing spectrum of disease-causing mutations and further define the genotype-phenotype correlations.METHODS: A Chinese STGD family and 200 normal controls were collected. Whole exome sequencing(WES) and bioinformatics analysis were performed to find the pathogenic gene mutation. Physico-chemical parameters of mutant and wildtype proteins were computed by Prot Param tool. Domains analysis was performed by SMART online software. HOPE online software was used to analyze the structural effects of mutation. Immunofluorescence, quantitative real-time polymerase chain reaction and Western blotting were used for expression analysis.RESULTS: Using WES, a novel homozygous mutation(NM_000350: c.G3190 C, p.G1064 R) in ABCA4 gene was identified. This mutation showed co-segregation with phenotype in this family. It was not found in the 200 unrelated health controls and absent from any databases. It was considered "Deleterious" as predicted by five function prediction softwares, and was highly conserved during evolution. ABCA4 was expressed highly in the human eye and mouse retina. The p.G1064 R was located in AAA domain, may force the local backbone into an incorrect conformation, disturb the local structure, and reduce the activity of ATPase resulting in the disease pathology. CONCLUSION: We define a novel pathogenic mutation(c.G3190 C of ABCA4) of STGD. This extends the existing spectrum of disease-causing mutations and further defines the genotype-phenotype correlations.
文摘Background: The majority of studies on the retina-specific ATP-binding casse tte transporter (ABCA4) gene have focussed on molecular genetic analysis; compar atively few studies have described the clinical aspects of ABCA4-associated ret inal disorders. In this study, we demonstrate the spectrum of retinal dystrophie s associated with ABCA4 gene mutations. Methods: Nine well-documented patients representing distinct phenotypes in the continuum of ABCA4-related disorders we re selected. All patients received an extensive ophthalmologic evaluation, inclu ding kinetic perimetry, fluorescein angiography, and electroretinography (ERG). Mutation analysis had been performed previously with the genotyping microarray ( ABCR400 chip) and/or single-strand conformation polymorphism analysis in combin ation with direct DNA sequencing. Results: In all patients, at least one patholo gic ABCA4 mutation was identified. Patient 10034 represented the mild end of the phenotypic spectrum, demonstrating exudative age-related macular degeneration (AMD). Patient 24481 received the diagnosis of late-onset fundus flavimaculatus (FFM), patient 15168 demonstrated the typical FFM phenotype, and patient 19504 had autosomal recessive Stargardt disease (STGD1). Patients 11302 and 7608 exhib ited progression from FFM/STGD1 to cone-rod dystrophy (CRD). A more typical CRD phenotype was found in patients 15680 and 12608. Finally, the most severe ABCA4 -associated phenotype was retinitis pigmentosa (RP) in patient 11366. This phen otype was characterised by extensive atrophy with almost complete loss of periph eral and central retinal functions. Conclusion: We describe nine patients during different stages of disease progression; together, these patients form a contin uum of ABCA4-associated phenotypes. Besides characteristic disorders such as FF M/STGD1, CRD and RP, intermediate phenotypes may be encountered. Moreover, as th e disease progresses, marked differences may be observed between initially compa rable phenotypes. In contrast, distinctly different phenotypes may converge to a similar final stage, characterised by extensive chorioretinal atrophy and very low visual functions. The identified ABCA4 mutations in most, but not all, patie nts were compatible with the resulting phenotypes, as predicted by the genotype -phenotype model for ABCA4-associated disorders. With the advent of therapeuti c options, recognition by the general ophthalmologist of the various retinal phe notypes associated with ABCA4 mutations is becoming increasingly important.
文摘目的研究全基因组甲基化对心力衰竭患者心肌基因表达的影响。方法取心脏移植中供体左心室心肌标本8例作为正常对照组,行心脏移植的心力衰竭患者自身左心室心肌标本14例作为实验组,提取基因组基因通过甲基化DNA免疫共沉淀结合甲基化芯片技术(methylated DNA immunoprecipitation-chip,MeDIP-chip)及基因表达谱芯片进行高通量的快速筛选。然后,得到MeDIP-chip初筛后的2个甲基化异常基因abca4和cd200进行亚硫酸氢钠测序PCR。结果疾病组abca4基因启动子区甲基化率为85.5%,正常组基因启动子区甲基化率为91.2%;疾病组基因启动子区甲基化率比正常组基因启动子区甲基化率低5.7%,心衰组cd200基因启动子区甲基化率为50.5%,正常组基因启动子区甲基化率为57.1%。结论 abca4和cd200启动子区甲基化改变会影响自身的基因表达量。心衰时DNA启动子区甲基化会发生改变,并且DNA启动子区的甲基化会伴随着基因表达量的改变。
基金This work was funded by the Aravind Eye Care System-Madurai,India.
文摘Background:Stargardt disease 1(STGD1;MIM 248200)is a monogenic form of autosomal recessive genetic disease caused by mutation in ABCA4.This gene has a major role in hydrolyzing N-retinylidene-phosphatidylethanolamine to all-trans-retinal and phosphatidylethanolamine.The purpose of this study is to identify the frequency of putative disease-causing mutations associated with Stargardt disease in a South Indian population.Methods:A total of 28 clinically diagnosed Stargardt-like phenotype patients were recruited from south India.Ophthalmic examination of all patients was carefully carried out by a retina specialist based on the stages of fundus imaging and ERG grouping.Genetic analysis of ABCA4 was performed for all patients using Sanger sequencing and clinical exome sequencing.Results:This study identified disease-causing mutations in ABCA4 in 75%(21/28)of patients,7%(2/28)exhibited benign variants and 18%(5/28)were negative for the disease-causing mutation.Conclusion:This is the first study describing the genetic association of ABCA4 disease-causing mutation in South Indian Stargardt 1 patients(STGD1).Our findings highlighted the presence of two novel missense mutations and an(in/del,single base pair deletion&splice variant)in ABCA4.However,genetic heterogeneity in ABCA4 mutants requires a larger sample size to establish a true correlation with clinical phenotype.
