Objective To explore the regulatory effect of fragile X mental retardation protein （FMRP） on the translation of microtubule associated protein 1B （MAP1B）. Methods The expressions of MAP1B protein and MAP1B mRNA in...Objective To explore the regulatory effect of fragile X mental retardation protein （FMRP） on the translation of microtubule associated protein 1B （MAP1B）. Methods The expressions of MAP1B protein and MAP1B mRNA in the brains of 1-week and 6-week old fragile X mental retardation-1 （FmrI） knockout （KO） mice were investigated by immunohistochemistry, Western blot, and in situ hybridization, with the age-matched wild type mice （WT） as controls. Results The mean optical density （MOD） of MAP1B was significantly decreased in each brain region in KO6W compared with WT6W, whereas in KO1W, this decrease was only found in the hippocampus and cerebellum. MAP1B in 6-week mice was much less than that in 1-week mice of the same genotype. The results of Western blot and in situ hybridization showed that MAP1B protein and MAP1B mRNA were significantly decreased in the hippocampus of both KO1W and KO6W. Conclusion The decreased MAP1B protein and MAP1B mRNA in the Fmrl knockout mice indicate that FMRP may positively regulate the expression of MAP1B.展开更多
More than 40 CGG expansions in the 5' noncoding region of the fragile X mental retardation 1(FMR1)gene of the X chromosome give rise to several distinct clinical phenotypes, depending on the size of the expansion....More than 40 CGG expansions in the 5' noncoding region of the fragile X mental retardation 1(FMR1)gene of the X chromosome give rise to several distinct clinical phenotypes, depending on the size of the expansion. First, more than 200 CGG expansions(full mutation) cause an inherited mental retardation called fragile X syndrome. Second, CGG expansions between55 and 199(premutation) cause a disorder called fragile X-associated tremor/ataxia syndrome(FXTAS) which typically includes intention tremor, ataxia and specific magnetic resonance imaging(MRI) findings. Indeed, it could develop parkinsonism although it usually shows features of postsynaptic parkinsonism. Finally, CGG expansions between 41 and 54 CGG(gray zone) are not consider normal but rarely develops abnormal neurological conditions. In this sense, the aim of this study is to report two atypical cases associated with CGG expansions of the FMR1 gene. First, a FMR1 premutation alleles carrier with an unusual phenotype, such as a presynaptic parkinsonism indistinguishable from Parkinson disease(PD) and a FMR1 gray zone alleles carrier presented with neurological features, namely hand tremor, parkinsonism and ataxia, usually described in FXTAS, as well as orthostatic tremor. We conclude that,on the one hand, FMR1 premutation alleles might cause two phenotypes of parkinsonism, such as a presynaptic phenotype, indistinguishable from PD, and a postsynaptic phenotype, associated with clinical features of FXTAS. On the other hand, although FMR1 gray zone alleles carriers were believed to have no abnormal neurological conditions, our study supports that they could develop FXTAS and other neurological disorders such as orthostatic tremor which has not been reported before associated with the FMR1 gene.展开更多
脆性X综合征(Fragile X syndrome, FXS)是一种智力缺陷和自闭症谱系的单基因遗传疾病。位于Xq27.3染色体的Fmr1基因沉默,造成该基因编码的mRNA翻译抑制因子FMRP表达缺失,从而导致FXS患者神经系统发育障碍。本研究采用质粒转染293T细胞获...脆性X综合征(Fragile X syndrome, FXS)是一种智力缺陷和自闭症谱系的单基因遗传疾病。位于Xq27.3染色体的Fmr1基因沉默,造成该基因编码的mRNA翻译抑制因子FMRP表达缺失,从而导致FXS患者神经系统发育障碍。本研究采用质粒转染293T细胞获取AAV9-FMRP腺相关病毒载体,通过立体定位方法将AAV9-FMRP注射到成年Fmr1 KO小鼠侧脑室。免疫组化检测发现AAV9介导的FMRP可以在Fmr1 KO小鼠海马和顶叶皮层等脑组织中获得性表达;免疫荧光检测发现FMRP定位于小鼠海马神经元胞质。研究结果表明,通过腺相关病毒可以介导FMRP在成年Fmr1 KO小鼠脑组织中获得性表达。展开更多
脆性X相关性疾病(FragileXassociatedDisorders,FXD)是由脆性X智力低下蛋白(FragileXMental Retardation Protein,FMRP)部分或完全丧失引起的家族遗传性疾病。其中脆性X综合征(Fragile X syndrome,FXS)是遗传性智力残疾和自闭症的最常...脆性X相关性疾病(FragileXassociatedDisorders,FXD)是由脆性X智力低下蛋白(FragileXMental Retardation Protein,FMRP)部分或完全丧失引起的家族遗传性疾病。其中脆性X综合征(Fragile X syndrome,FXS)是遗传性智力残疾和自闭症的最常见原因之一,其发病率仅次于唐氏综合征,占非特发性智力低下患者的2%-6%,在X连锁智力低下患者中占40%。FXD临床表现不典型,遗传方式多样化。本文将从FXD的临床表现,FMR1基因及其致病机制,FMRP结构及其对转录翻译过程中的影响等方面进行综述。展开更多
In eukaryotic cells, gene activity is not directly reflected by protein levels because mRNA processing, transport, stability, and translation are co- and post-transcriptionally regulated. These processes, collectively...In eukaryotic cells, gene activity is not directly reflected by protein levels because mRNA processing, transport, stability, and translation are co- and post-transcriptionally regulated. These processes, collectively known as the ribonome, are tightly controlled and carried out by a plethora of trans-acting RNA-binding proteins （RBPs） that bind to specific cis elements throughout the RNA sequence. Within the nervous system, the role of RBPs in brain function turns out to be essential due to the architectural complexity of neurons exemplified by a relatively small somal size and an extensive network of projections and connections, Thus far, RBPs have been shown to be indispensable for several aspects of neurogenesis, neurite outgrowth, synapse formation, and plasticity. Consequently, perturbation of their function is central in the etiology of an ever-growing spectrum of neurological diseases, including fragile X syndrome and the neurodegenerative disorders frontotemporal lobar degeneration and amyotrophic lateral sclerosis.展开更多
文摘Objective To explore the regulatory effect of fragile X mental retardation protein （FMRP） on the translation of microtubule associated protein 1B （MAP1B）. Methods The expressions of MAP1B protein and MAP1B mRNA in the brains of 1-week and 6-week old fragile X mental retardation-1 （FmrI） knockout （KO） mice were investigated by immunohistochemistry, Western blot, and in situ hybridization, with the age-matched wild type mice （WT） as controls. Results The mean optical density （MOD） of MAP1B was significantly decreased in each brain region in KO6W compared with WT6W, whereas in KO1W, this decrease was only found in the hippocampus and cerebellum. MAP1B in 6-week mice was much less than that in 1-week mice of the same genotype. The results of Western blot and in situ hybridization showed that MAP1B protein and MAP1B mRNA were significantly decreased in the hippocampus of both KO1W and KO6W. Conclusion The decreased MAP1B protein and MAP1B mRNA in the Fmrl knockout mice indicate that FMRP may positively regulate the expression of MAP1B.
文摘More than 40 CGG expansions in the 5' noncoding region of the fragile X mental retardation 1(FMR1)gene of the X chromosome give rise to several distinct clinical phenotypes, depending on the size of the expansion. First, more than 200 CGG expansions(full mutation) cause an inherited mental retardation called fragile X syndrome. Second, CGG expansions between55 and 199(premutation) cause a disorder called fragile X-associated tremor/ataxia syndrome(FXTAS) which typically includes intention tremor, ataxia and specific magnetic resonance imaging(MRI) findings. Indeed, it could develop parkinsonism although it usually shows features of postsynaptic parkinsonism. Finally, CGG expansions between 41 and 54 CGG(gray zone) are not consider normal but rarely develops abnormal neurological conditions. In this sense, the aim of this study is to report two atypical cases associated with CGG expansions of the FMR1 gene. First, a FMR1 premutation alleles carrier with an unusual phenotype, such as a presynaptic parkinsonism indistinguishable from Parkinson disease(PD) and a FMR1 gray zone alleles carrier presented with neurological features, namely hand tremor, parkinsonism and ataxia, usually described in FXTAS, as well as orthostatic tremor. We conclude that,on the one hand, FMR1 premutation alleles might cause two phenotypes of parkinsonism, such as a presynaptic phenotype, indistinguishable from PD, and a postsynaptic phenotype, associated with clinical features of FXTAS. On the other hand, although FMR1 gray zone alleles carriers were believed to have no abnormal neurological conditions, our study supports that they could develop FXTAS and other neurological disorders such as orthostatic tremor which has not been reported before associated with the FMR1 gene.
文摘脆性X相关性疾病(FragileXassociatedDisorders,FXD)是由脆性X智力低下蛋白(FragileXMental Retardation Protein,FMRP)部分或完全丧失引起的家族遗传性疾病。其中脆性X综合征(Fragile X syndrome,FXS)是遗传性智力残疾和自闭症的最常见原因之一,其发病率仅次于唐氏综合征,占非特发性智力低下患者的2%-6%,在X连锁智力低下患者中占40%。FXD临床表现不典型,遗传方式多样化。本文将从FXD的临床表现,FMR1基因及其致病机制,FMRP结构及其对转录翻译过程中的影响等方面进行综述。
基金funded by grants from the Greek General Secretariat for Research and Development,Ministry of Education
文摘In eukaryotic cells, gene activity is not directly reflected by protein levels because mRNA processing, transport, stability, and translation are co- and post-transcriptionally regulated. These processes, collectively known as the ribonome, are tightly controlled and carried out by a plethora of trans-acting RNA-binding proteins （RBPs） that bind to specific cis elements throughout the RNA sequence. Within the nervous system, the role of RBPs in brain function turns out to be essential due to the architectural complexity of neurons exemplified by a relatively small somal size and an extensive network of projections and connections, Thus far, RBPs have been shown to be indispensable for several aspects of neurogenesis, neurite outgrowth, synapse formation, and plasticity. Consequently, perturbation of their function is central in the etiology of an ever-growing spectrum of neurological diseases, including fragile X syndrome and the neurodegenerative disorders frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
