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中华医学杂志 1991年第1期71卷 48-49页

作者：贺明伟夏家辉李麓芸戴和平湖南医科大学医学遗传学研究室

我们采用能同时显示脆性x[fra(x)]和失活x染色体的方法,对两个家系中的两个女性患者及其表型正常的携带者母亲进行了比较。 1.主要临床表现: 例1 女性,年龄6岁9个月。智力发育差,不能完整表达主观意念,对10以内的数字概念不清。检查:眼... 详细信息

我们采用能同时显示脆性x[fra(x)]和失活x染色体的方法,对两个家系中的两个女性患者及其表型正常的携带者母亲进行了比较。 1.主要临床表现: 例1 女性,年龄6岁9个月。智力发育差,不能完整表达主观意念,对10以内的数字概念不清。检查:眼距稍宽,后发际较低,腭弓高。脑电图和头部CT检查未见异常。中国韦氏幼儿智力测验:全智商

关键词：脆性x综合征/遗传学智力障碍/遗传学

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A novel RNA-binding nuclear protein that interacts with the fragile x mental retardation (FMR1) protein

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HUMAN MOLECULAR GENETICS 1999年第13期8卷 2557-2566页

作者： Bardoni, B Schenck, A Mandel, JL ULP CNRS INSERM Inst Genet & Biol Mol Cellulaire F-67404 Illkirch Graffenstaden CU Strasbourg France

Silenced expression of the FMR1 gene is responsible for the fragile x syndrome. The FMR1 gene codes for an RNA binding protein (FMRP), which can shuttle between the nucleus and the cytoplasm and is found associated to polysomes in the cytoplasm, By two-hybrid assay in yeast, we identified a novel protein interacting with FMRP: nuclear FMRP interacting protein (NUFIP). NUFIP mRNA expression is strikingly similar to that of the FMR1 gene in neurones of cortex, hippocampus and cerebellum, At the subcellular level, NUFIP colocalizes with nuclear isoforms of FMRP in a dot-like pattern. NUFIP presents a C2H2 zinc finger motif and a nuclear localization signal, but has no homology to known proteins and shows RNA binding activity in vitro, NUFIP does not interact with the FMRP homologues encoded by the FxR1 and FxR2 genes. Thus, these results indicate a specific nuclear role for FMRP.

关键词：氨基酸序列脑/代谢 COS细胞细胞核/代谢荧光抗体技术脆性x智力低下蛋白质脆性x综合征/遗传学基因表达 HeLa细胞原位杂交精神发育迟滞/遗传学显微镜检查共焦分子序列数据神经组织蛋白质类/遗传学神经组织蛋白质类/代谢核蛋白质类/遗传学核蛋白质类/代谢 RNA结合蛋白质类/遗传学 RNA结合蛋白质类/代谢重组蛋白质类/代谢双杂交系统技术酵母菌/遗传学锌指动物人类小鼠

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(Over)correction of FMR1 deficiency with YAC transgenics: behavioral and physical features

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HUMAN MOLECULAR GENETICS 2000年第8期9卷 1145-1159页

作者： Peier, AM McIlwain, KL Kenneson, A Warren, ST Paylor, R Nelson, DL Baylor Coll Med Dept Mol & Human Genet Houston TX 77030 USA Emory Univ Sch Med Dept Chem Atlanta GA 30322 USA Emory Univ Sch Med Howard Hughes Med Inst Atlanta GA 30322 USA

Fragile x syndrome is a common cause of mental retardation involving loss of expression of the FMR1 gene. The role of FMR1 remains undetermined but the protein appears to be involved in RNA metabolism. Fmr1 knock-out mice exhibit a phenotype with some similarities to humans, such as macroorchidism and behavioral abnormalities. As a step toward understanding the function of FMR1 and the determination of the potential for therapeutic approaches to fragile x syndrome, yeast artificial chromosome (YAC) transgenic mice were generated in order to determine whether the Fmr1 knockout mouse phenotype could be rescued. Several transgenic lines were generated that carried the entire FMR1 locus with extensive amounts of flanking sequence. We observed that the YAC transgene supported production of the human protein (FMRP) which was present at levels 10 to 15 times that of endogenous protein and was expressed in a cell- and tissue-specific manner. Macroorchidism was absent in knockout mice carrying the YAC transgene indicating functional rescue by the human protein. Given the complex behavioral phenotype in fragile x patients and the mild phenotype previously reported for the Fmr1 knockout mouse, we performed a more thorough evaluation of the Fmr1 knockout phenotype using additional behavioral assays that had not previously been reported for this animal model. The mouse displayed reduced anxiety-related responses with increased exploratory behavior. FMR1 YAC transgenic mice overexpressing the human protein did produce opposing behavioral responses and additional abnormal behaviors were also observed. These findings have significant implications for gene therapy for fragile x syndrome since overexpression of the gene may harbor its own phenotype.

关键词：脑/代谢染色体人工酵母外显子脆性x智力低下蛋白质脆性x综合征/遗传学脆性x综合征/治疗基因疗法精神障碍/遗传学小鼠基因敲除小鼠转基因运动活动神经组织蛋白质类/缺乏神经组织蛋白质类/遗传学神经组织蛋白质类/生理学表型 RNA结合蛋白质类重组蛋白质类/生物合成睾丸/代谢动物人类男(雄)性小鼠

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The clinical significance of fragile sites on human chromosomes

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CLINICAL GENETICS 2000年第3期58卷 157-161页

作者： Sutherland, GR Baker, E Womens & Childrens Hosp Dept Cytogenet & Mol Genet Ctr Med Genet Adelaide SA 5006 Australia

Fragile x syndrome is now a well established common clinical entity and most of those who are aware of the condition probably know that it takes its name from a rare fragile site (FRAxA) on the x chromosome. This is the best known fragile site and its clinical significance is clear. Similar, but a little less known is FRAxE, a fragile site close to that associated with fragile x syndrome, but in this case associated with a mild form of non-specific x-linked mental retardation. These are the only two fragile sites that are unequivocally of clinical significance. A fragile site within the CBL2 oncogene on chromosome ii has been mapped very close to the deletion breakpoint in a handful of patients with Jacobsen syndrome. It is doubtful that parents with FRA11B are at increased risk of having children with Jacobsen syndrome, but this cannot be ruled out. The common fragile sites have been implicated in oncogenesis since shortly after their discovery in the early 1980s. While a couple of these are within genes that have been implicated in cancer it is unclear whether either the fragile sites, or the genes in which they are located are important in cancer. It may be that the common fragile sites are regions of genomic instability and that this instability is increased in malignant cells, analogous to the enhanced instability seen at microsatellite loci in a number of tumours. Since we all have the common fragile sites there is no suggestion that they give anyone an increased risk of developing malignant disease. In dealing with patients who are found to have fragile sites, other than FRAxA, FRAxE and possibly FRA11B, considerable reassurance can be given that they are not at increased risk of having children with congenital disease or developing disease themselves because of their fragile sites.

关键词：染色体畸变/分类染色体畸变/诊断染色体畸变/遗传学染色体障碍染色体脆性位点染色体脆性/遗传学脆性x综合征/遗传学疾病遗传易感性智力障碍/遗传学产前诊断 x染色体/遗传学人类

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The x chromosome and ovarian failure

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CLINICAL ENDOCRINOLOGY 1999年第6期51卷 673-679页

作者： Davison, RM Davis, CJ Conway, GS UCL Cobboid Labs Div Endocrinol Dept MedSch Med London England

Presents various proposed candidate genes for ovarian failure on the x chromosome. Evidence for x chromosome genes causing ovarian failure; Candidate genes for premature ovarian failure on the x chromosome; x-inactiva... 详细信息

关键词：衔接蛋白质类信号转导载体蛋白质类/遗传学 DNA结合蛋白质类/遗传学剂量补偿作用遗传学脆性x综合征/遗传学基因缺失高迁移率族蛋白质类/遗传学卵巢/畸形原发性卵巢功能不全/遗传学受体血管紧张素 2型受体血管紧张素/遗传学受体 FSH/遗传学 SOxB1转录因子类转录因子 x染色体锌指/遗传学动物女(雌)性人类男(雄)性

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Fragile x CGG repeat structures among African-Americans: identification of a novel factor responsible for repeat instability

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HUMAN MOLECULAR GENETICS 2000年第12期9卷 1759-1769页

作者： Crawford, DC Zhang, FP Wilson, B Warren, ST Sherman, SL Emory Univ Sch Med Dept Genet Atlanta GA 30322 USA Emory Univ Sch Med Dept Biochem Atlanta GA 30322 USA Emory Univ Sch Med Dept Pediat Atlanta GA 30322 USA Howard Hughes Med Inst Atlanta GA 30322 USA

The cryptic CGG repeat responsible for the fragile x syndrome, located in the 5'-UTR of FMR1, is unique compared with the many other triplet repeat-causing diseases, making it ideal for identifying factors involved in repeat expansion that may be common to other triplet repeat diseases. To date, a number of factors have been identified which may influence repeat instability, including the number and position of interspersed AGGs, length of the 3' pure CGG repeat and haplotype background, However, nearly all such data were derived from studies of Caucasians, Using a large African-American population, we present the only comprehensive examination of factors associated with CGG repeat instability in a non-Caucasian population. Among Caucasians, susceptible alleles were thought to come from those in the intermediate repeat range (41-60 repeats);however, we find that susceptible alleles may come from a larger repeat pool (35-60 repeats) and are better defined by their pure CGG repeat and/or presence of only one AGG interruption, These results demonstrate the existence of different susceptible alleles among world populations and may account for the similar prevalence of the fragile x syndrome in African-Americans compared with Caucasians despite the lower frequency of intermediate sized alleles in the African-American population. Finally, we show that repeat structures among unaffected African-Americans with the most frequent fragile x haplotype background are either pure or contain a single distal interruption. We propose that the lack of a proximal most interruption is a novel factor involved in CGG repeat instability.

关键词： 5'非翻译区非洲裔美国人非洲大陆世系人群/遗传学等位基因脆性x智力低下蛋白质脆性x综合征/遗传学遗传标记神经组织蛋白质类/遗传学系谱 RNA稳定性/遗传学 RNA结合蛋白质类末端重复序列三核苷酸重复女(雌)性人类男(雄)性

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Fragile x syndrome in Calcutta, India

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ANNALS OF CLINICAL BIOCHEMISTRY 2001年第3期38卷 264-271页

作者： Saha, S Karmakar, P Chatterjee, C Banerjee, D Das, S Dasgupta, UB Univ Calcutta Dept Biophys Mol Biol & Genet Kolkata 700009 W Bengal India Postgrad Inst Med Res Dept Pathol Kolkata 700021 W Bengal India Bangur Inst Neurol Dept Neurol Kolkata 700025 W Bengal India

Fragile-x-linked mental retardation usually results from amplification of the CGG repeat in the 5' untranslated region of the FMR1 gene. To assess the extent of variation of the CGG repeat in the population from the eastern region of India we studied 98 mentally retarded individuals living in and around Calcutta and identified 21 distinct alleles ranging in size from 8 to 44 CGG repeats. A repeat size of 28 was the most frequent. this value is different from the most frequent repeat size found in other studies. indicating a racial or ethnic variation. Patients with the clinical features of the syndrome have been found to carry expanded CGG repeats. Thus. it can be inferred that the expansion of CGG repeats may be a frequent cause of the syndrome in our population.

关键词：等位基因印迹法 DNA CpG岛 DNA甲基化脆性x综合征/遗传学印度镶嵌现象突变系谱聚合酶链反应三核苷酸重复青少年成年人儿童女(雌)性人类男(雄)性中年人

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Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene

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HUMAN MOLECULAR GENETICS 1999年第12期8卷 2317-2323页

作者： Chiurazzi, P Pomponi, MG Pietrobono, R Bakker, CE Neri, G Oostra, BA Univ Cattolica Ist Genet Med I-00168 Rome Italy Assoc Anni Verdi Ctr Ricerche Disabil Mentale & Motoria I-00168 Rome Italy Erasmus Univ Dept Clin Genet NL-3000 DR Rotterdam Netherlands Erasmus Univ Ctr Biomed Genet NL-3000 DR Rotterdam Netherlands

Most fragile x syndrome patients have expansion of a (CGG)(n) sequence with >200 repeats (full mutation) in the FMR1 gene responsible for this condition, Hypermethylation of the expanded repeat and of the FMR1 promoter is almost always present and apparently suppresses transcription, resulting in absence of the FMR1 protein. We recently showed that transcriptional reactivation of FMR1 full mutations can be achieved by inducing DNA demethylation with 5-azadeoxycytidine (5-azadC). The level of histone acetylation is another important factor in regulating gene expression;therefore, we treated lymphoblastoid cell lines of non-mosaic full mutation patients with three drugs capable of inducing histone hyperacetylation, We observed a consistent, although modest, reactivation of the FMR1 gene with 4-phenylbutyrate, sodium butyrate and trichostatin A, as shown by RT-PCR, However, we report that combining these drugs with 5-azadC results in a 2- to 5-fold increase in FMR1 mRNA levels obtained with 5-azadC alone, thus showing a marked synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of FMR1 full mutations.

关键词：乙酰化作用阿扎胞苷/类似物和衍生物阿扎胞苷/药理学碱基序列细胞系 DNA甲基化 DNA引物酶抑制剂/药理学脆性x智力低下蛋白质脆性x综合征/遗传学组蛋白类/代谢神经组织蛋白质类/遗传学 RNA结合蛋白质类逆转录聚合酶链反应人类男(雄)性

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RNAs that interact with the Fragile x syndrome RNA binding protein FMRP

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2000年第3期275卷 973-980页

作者： Sung, YJ Conti, J Currie, JR Brown, WT Denman, RB New York State Inst Basic Res Dev Disabil Dept Mol Biol Staten Isl NY 10314 USA New York State Inst Basic Res Dev Disabil Dept Human Genet Staten Isl NY 10314 USA

The Fragile x protein FMRP is an RNA binding protein whose targets are not well known;yet, these RNAs may play an integral role in the disease's etiology, Using a biotinylated-FMRP affinity resin, we isolated RNAs from the parietal cortex of a normal adult that bound FMRP, These RNAs were amplified by differential display (DDRT-PCR) and cloned and their identities determined. Nine candidate RNAs were isolated;five RNAs, including FMR1 mRNA, encoded known proteins. Four others were novel. The specificity of binding was demonstrated for each candidate RNA. The domains required for binding a subset of the RNAs were delineated using FMRP truncation mutant proteins and it was shown that only the KH2 domain was required for binding. Binding occurred independently of homoribopolymer binding to the C-terminal arginine-glycine-rich region (RGG box), suggesting that FMRP may bind multiple RNAs simultaneously. (C) 2000 Academic Press.

关键词：碱基序列结合竞争性生物素化作用脑/代谢色谱法亲和克隆分子脆性x智力低下蛋白质脆性x综合征/遗传学脆性x综合征/代谢分子序列数据突变神经组织蛋白质类/遗传学神经组织蛋白质类/代谢蛋白质结合 RNA 信使/分析 RNA 信使/遗传学 RNA 信使/分离和提纯 RNA 信使/代谢 RNA结合蛋白质类/遗传学 RNA结合蛋白质类/代谢动物人类小鼠

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Comparison of FMR1-protein expression in lymphocytes, methylation pattern in Southern blot analysis, and IQ values in three sisters with the fragile x syndrome

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AMERICAN JOURNAL OF MEDICAL GENETICS 2002年第4期107卷 344-345页

作者： Vink, GR Froster, UG Univ Leipzig Inst Human Genet Leipzig Germany

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