Aim Fragile X mental retardation protein （FMRP） is an RNA-binding protein important for the control of translation and synaptic function. The mutation or silencing of FMRP causes Fragile X syndrome （FXS） , which l...Aim Fragile X mental retardation protein （FMRP） is an RNA-binding protein important for the control of translation and synaptic function. The mutation or silencing of FMRP causes Fragile X syndrome （FXS） , which leads to intellectual disability and social impairment. γ-aminobutyric acid （GABA） is the major inhibitory neuro- transmitter of the mammalian central nervous system, and its metabotropic GABAB receptor has been implicated in various mental disorders. The GABAB receptor agonist baclofen has been shown to improve FXS symptoms in a mouse model and in human patients, suggesting the role of GABAB receptor on FMRP regulation. Here we investi- gated the signaling events linking the GABAB receptor and FMRP. Methods Western blot was used in this study to detect protein expression and kinase phosphorylation in cerebellar granule neurons. For key molecules in signal- ling pathway, RNAi was used in MEFs to confirm the results in neurons. Results GABAB receptor activation up- regulated cAMP response element binding protein-dependent Fmrp expression in cultured mouse cerebellar granule neurons via two distinct mechanisms： the transactivation of insulin-like growth factor-1 receptor and activation of protein kinase C. In addition, a positive allosteric modulator of the GABAB receptor, CGP7930, stimulated Fmrp expression in neurons. Conclusion These results suggest a role for GABAB receptor in Fmrp regulation and a po- tential interest of GABAB receptor signaling in FXS improvement.展开更多
Fragile X syndrome （FXS） is one of the most prevalent mental retardations. It is mainly caused by the loss of fragile X mental retardation protein （FMRP）. FMRP is an RNA binding protein and can regulate the transl...Fragile X syndrome （FXS） is one of the most prevalent mental retardations. It is mainly caused by the loss of fragile X mental retardation protein （FMRP）. FMRP is an RNA binding protein and can regulate the translation of its binding RNA, thus regulate several signaling pathways. Many FXS patients show high susceptibility to epilepsy. Epilepsy is a chronic neurological disorder which is characterized by the recurrent appearance of spontaneous seizures due to neuronal hyperactivity in the brain. Both the abnormal activation of several signaling pathway and morphological abnormality that are caused by the loss of FMRP can lead to a high susceptibility to epilepsy. Combining with the research progresses on both FXS and epilepsy, we outlined the possible mechanisms of high susceptibility to epilepsy in FXS and tried to give a prospect on the future research on the mechanism of epilepsy that happened in other mental retardations.展开更多
AIM: To investigate the prevalence of fragile X syndrome(FXS) in intellectually disabled male and female Indonesians.METHODS: This research is an extension of a previously reported study on the identification of chrom...AIM: To investigate the prevalence of fragile X syndrome(FXS) in intellectually disabled male and female Indonesians.METHODS: This research is an extension of a previously reported study on the identification of chromosomal aberrations in a large cohort of 527 Indonesians with intellectual disability(ID). In this previous study,87 patients had a chromosomal abnormality, five of whom expressed fragile sites on Xq27.3. Since FXS cannot always be identified by cytogenetic analysis, molecular testing of the fragile X mental retardation 1 CGG repeat was performed in 440 samples. The testing was also conducted in the five previously identified samples to confirm the abnormality. In total, a molecular study was conducted in 445 samples(162 females and 283 males).RESULTS: In the cohort of Indonesian ID population, the prevalence of FXS is 9/527(1.7%). The prevalence in males and females is 1.5%(5/329) and 2%(4/198), respectively. Segregation analysis in the families and X-inactivation studies were performed. We performed the first comprehensive genetic survey of a representative sample of male and female ID individuals from institutions and special schools in Indonesia. Our findings show that a comprehensive study of FXS can be performed in a developing country like Indonesia where diagnostic facilities are limited.CONCLUSION: The prevalence of FXS is equal in females and males in our study, which suggests that the prevalence of FXS in females could be underestimated.展开更多
脆性X综合征(fragile X syndrome,FXS)是FMR1基因CGG异常重复扩增导致的疾病。本文报告1对经基因检测诊断为FXS的兄弟,2例患者分别为15岁和14岁,均存在语言障碍、智力障碍、注意力缺陷障碍、孤独症谱系障碍和FXS特征性面容等临床表现,...脆性X综合征(fragile X syndrome,FXS)是FMR1基因CGG异常重复扩增导致的疾病。本文报告1对经基因检测诊断为FXS的兄弟,2例患者分别为15岁和14岁,均存在语言障碍、智力障碍、注意力缺陷障碍、孤独症谱系障碍和FXS特征性面容等临床表现,其中先证者伴有罕见的晚发性癫痫发作,经左乙拉西坦治疗效果良好,而其弟弟经反复随访未见脑电图异常。该对病例提示FXS临床表型具有多样性和异质性。展开更多
Fragiie X syndrome is the most common form of inherited mental retardation disease, resulting from absent of expression of its disease gene FMR1. To study the function of the fragiie X mental retardation protein (FMRP...Fragiie X syndrome is the most common form of inherited mental retardation disease, resulting from absent of expression of its disease gene FMR1. To study the function of the fragiie X mental retardation protein (FMRP) through protein/protein interaction, a mouse embryo cDNA library was screened by the yeast two-hybrid system. A clone was found to interact specifically with FMRP. The cDNA of this clone ( Genbank accession number af102875 ) encoded a protein highly homologous to human G/T mismatch-specific DNA thymine glycosylase ( hTDG ). Interactions between various alternatively spliced FMRP isoforms and a series of mTDG deletion proteins were further studied in the yeast two-hybrid system and their interaction amino acid regions were determined. interaction between FMRP and TDG existed inside exon 13 of FMRP ( amino acid residue 397-425 ) and around amino acid residue 122-346 of TDG. These results will be helpful to the study of the biological role of FMRP.展开更多
Recently, Khayachi et al.;showed that fragile X mental retardation protein （FMRP） is an active substrate of the small ubiquitin-like modifier （SUMO） pathway in neurons.FMRP SUMOylation is induced by the activation...Recently, Khayachi et al.;showed that fragile X mental retardation protein （FMRP） is an active substrate of the small ubiquitin-like modifier （SUMO） pathway in neurons.FMRP SUMOylation is induced by the activation of metabotropic glutamate receptors （mGlu5Rs）. FMRP展开更多
Homoeostatic regulation of the light sensor, rhodopsin, is critical for the maintenance of light sensitivity and survival of photore- ceptors. The major fly rhodopsin, Rhl, undergoes light-induced endocytosis and degr...Homoeostatic regulation of the light sensor, rhodopsin, is critical for the maintenance of light sensitivity and survival of photore- ceptors. The major fly rhodopsin, Rhl, undergoes light-induced endocytosis and degradation, but its protein and mRNA levels remain constant during light/dark cycles. It is not clear how translation of Rhl is regulated. Here, we show that adult photorecep- tors maintain a constant, abundant quantity of ninaE mRNA, which encodes Rhl. We demonstrate that the Fmrl protein associ- ates with ninaE mRNA and represses its translation. Further, light exposure triggers a calcium-dependent dephosphorylation of Fmrl, which relieves suppression of Rhl translation. We demonstrate that Mts, the catalytic subunit of protein phosphatase 2A （PP2A）, mediates light-induced Fmrl dephosphorylation in a regulatory B subunit of PP2A （CKa）-dependent manner. Finally, we show that blocking light-induced Rhl translation results in reduced light sensitivity. Our results reveal the molecular mechanism of Rhl homoeostasis and physiological consequence of Rhl dysregulation.展开更多
Background: The aim of this study is to investigate the prevalence of the fragile X mental retardation 1(FMR1) gene premutation in Han Chinese women with primary ovarian insufficiency(POI) using a rapid and cost-effec...Background: The aim of this study is to investigate the prevalence of the fragile X mental retardation 1(FMR1) gene premutation in Han Chinese women with primary ovarian insufficiency(POI) using a rapid and cost-effective method. Methods: A total of 153 Han Chinese women with sporadic POI were systematically analyzed for trinucleotide repeats within the FMR1 gene. We employed an improved strategy to screen for cytosine-guanine-guanine repeats in the 5’ untranslated region of the FMR1 gene. Before using the previously reported Fragil Ease polymerase chain reaction(PCR) method for premutation identification, we developed a new cost-effective PCR-based method to exclude most of the normal allele carriers during the initial screening stage. Results: In our initial screening, 62.1% of women with POI were found to carry heterozygous normal alleles of FMR1, which were recognized by our sensitive and cost-effective method. The remaining women were further screened for the presence of the FMR1 premutation. We identified a Han Chinese woman with a premutation allele of FMR1 out of 153 sporadic POI women(0.7%). Conclusions: The frequent FMR1 premutation in Caucasian individuals with POI may not be a common genetic cause of sporadic POI in the Han Chinese population.展开更多
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
文摘Aim Fragile X mental retardation protein （FMRP） is an RNA-binding protein important for the control of translation and synaptic function. The mutation or silencing of FMRP causes Fragile X syndrome （FXS） , which leads to intellectual disability and social impairment. γ-aminobutyric acid （GABA） is the major inhibitory neuro- transmitter of the mammalian central nervous system, and its metabotropic GABAB receptor has been implicated in various mental disorders. The GABAB receptor agonist baclofen has been shown to improve FXS symptoms in a mouse model and in human patients, suggesting the role of GABAB receptor on FMRP regulation. Here we investi- gated the signaling events linking the GABAB receptor and FMRP. Methods Western blot was used in this study to detect protein expression and kinase phosphorylation in cerebellar granule neurons. For key molecules in signal- ling pathway, RNAi was used in MEFs to confirm the results in neurons. Results GABAB receptor activation up- regulated cAMP response element binding protein-dependent Fmrp expression in cultured mouse cerebellar granule neurons via two distinct mechanisms： the transactivation of insulin-like growth factor-1 receptor and activation of protein kinase C. In addition, a positive allosteric modulator of the GABAB receptor, CGP7930, stimulated Fmrp expression in neurons. Conclusion These results suggest a role for GABAB receptor in Fmrp regulation and a po- tential interest of GABAB receptor signaling in FXS improvement.
文摘Fragile X syndrome （FXS） is one of the most prevalent mental retardations. It is mainly caused by the loss of fragile X mental retardation protein （FMRP）. FMRP is an RNA binding protein and can regulate the translation of its binding RNA, thus regulate several signaling pathways. Many FXS patients show high susceptibility to epilepsy. Epilepsy is a chronic neurological disorder which is characterized by the recurrent appearance of spontaneous seizures due to neuronal hyperactivity in the brain. Both the abnormal activation of several signaling pathway and morphological abnormality that are caused by the loss of FMRP can lead to a high susceptibility to epilepsy. Combining with the research progresses on both FXS and epilepsy, we outlined the possible mechanisms of high susceptibility to epilepsy in FXS and tried to give a prospect on the future research on the mechanism of epilepsy that happened in other mental retardations.
基金Risbin-Iptekdok 2007/2008,Ministry of Health Republic of IndonesiaExcellent Scholarship(Beasiswa Unggulan Program),Foreign Scholarship(Beasiswa Luar Negeri),Directorate of Higher Education(DGHE)+1 种基金Ministry of National Education Republic of Indonesiathe PhD-fellowship Program of the Radboud University(RU-fellowship)
文摘AIM: To investigate the prevalence of fragile X syndrome(FXS) in intellectually disabled male and female Indonesians.METHODS: This research is an extension of a previously reported study on the identification of chromosomal aberrations in a large cohort of 527 Indonesians with intellectual disability(ID). In this previous study,87 patients had a chromosomal abnormality, five of whom expressed fragile sites on Xq27.3. Since FXS cannot always be identified by cytogenetic analysis, molecular testing of the fragile X mental retardation 1 CGG repeat was performed in 440 samples. The testing was also conducted in the five previously identified samples to confirm the abnormality. In total, a molecular study was conducted in 445 samples(162 females and 283 males).RESULTS: In the cohort of Indonesian ID population, the prevalence of FXS is 9/527(1.7%). The prevalence in males and females is 1.5%(5/329) and 2%(4/198), respectively. Segregation analysis in the families and X-inactivation studies were performed. We performed the first comprehensive genetic survey of a representative sample of male and female ID individuals from institutions and special schools in Indonesia. Our findings show that a comprehensive study of FXS can be performed in a developing country like Indonesia where diagnostic facilities are limited.CONCLUSION: The prevalence of FXS is equal in females and males in our study, which suggests that the prevalence of FXS in females could be underestimated.
文摘脆性X综合征(fragile X syndrome,FXS)是FMR1基因CGG异常重复扩增导致的疾病。本文报告1对经基因检测诊断为FXS的兄弟,2例患者分别为15岁和14岁,均存在语言障碍、智力障碍、注意力缺陷障碍、孤独症谱系障碍和FXS特征性面容等临床表现,其中先证者伴有罕见的晚发性癫痫发作,经左乙拉西坦治疗效果良好,而其弟弟经反复随访未见脑电图异常。该对病例提示FXS临床表型具有多样性和异质性。
文摘Fragiie X syndrome is the most common form of inherited mental retardation disease, resulting from absent of expression of its disease gene FMR1. To study the function of the fragiie X mental retardation protein (FMRP) through protein/protein interaction, a mouse embryo cDNA library was screened by the yeast two-hybrid system. A clone was found to interact specifically with FMRP. The cDNA of this clone ( Genbank accession number af102875 ) encoded a protein highly homologous to human G/T mismatch-specific DNA thymine glycosylase ( hTDG ). Interactions between various alternatively spliced FMRP isoforms and a series of mTDG deletion proteins were further studied in the yeast two-hybrid system and their interaction amino acid regions were determined. interaction between FMRP and TDG existed inside exon 13 of FMRP ( amino acid residue 397-425 ) and around amino acid residue 122-346 of TDG. These results will be helpful to the study of the biological role of FMRP.
基金supported by the National Natural Science Foundation of China (81503074)
文摘Recently, Khayachi et al.;showed that fragile X mental retardation protein （FMRP） is an active substrate of the small ubiquitin-like modifier （SUMO） pathway in neurons.FMRP SUMOylation is induced by the activation of metabotropic glutamate receptors （mGlu5Rs）. FMRP
文摘Homoeostatic regulation of the light sensor, rhodopsin, is critical for the maintenance of light sensitivity and survival of photore- ceptors. The major fly rhodopsin, Rhl, undergoes light-induced endocytosis and degradation, but its protein and mRNA levels remain constant during light/dark cycles. It is not clear how translation of Rhl is regulated. Here, we show that adult photorecep- tors maintain a constant, abundant quantity of ninaE mRNA, which encodes Rhl. We demonstrate that the Fmrl protein associ- ates with ninaE mRNA and represses its translation. Further, light exposure triggers a calcium-dependent dephosphorylation of Fmrl, which relieves suppression of Rhl translation. We demonstrate that Mts, the catalytic subunit of protein phosphatase 2A （PP2A）, mediates light-induced Fmrl dephosphorylation in a regulatory B subunit of PP2A （CKa）-dependent manner. Finally, we show that blocking light-induced Rhl translation results in reduced light sensitivity. Our results reveal the molecular mechanism of Rhl homoeostasis and physiological consequence of Rhl dysregulation.
基金supported by the National Key Research and Development Program of China(2016YFC0905100)the National Natural Science Foundation of China(31625015,31521003,and 31571297).
文摘Background: The aim of this study is to investigate the prevalence of the fragile X mental retardation 1(FMR1) gene premutation in Han Chinese women with primary ovarian insufficiency(POI) using a rapid and cost-effective method. Methods: A total of 153 Han Chinese women with sporadic POI were systematically analyzed for trinucleotide repeats within the FMR1 gene. We employed an improved strategy to screen for cytosine-guanine-guanine repeats in the 5’ untranslated region of the FMR1 gene. Before using the previously reported Fragil Ease polymerase chain reaction(PCR) method for premutation identification, we developed a new cost-effective PCR-based method to exclude most of the normal allele carriers during the initial screening stage. Results: In our initial screening, 62.1% of women with POI were found to carry heterozygous normal alleles of FMR1, which were recognized by our sensitive and cost-effective method. The remaining women were further screened for the presence of the FMR1 premutation. We identified a Han Chinese woman with a premutation allele of FMR1 out of 153 sporadic POI women(0.7%). Conclusions: The frequent FMR1 premutation in Caucasian individuals with POI may not be a common genetic cause of sporadic POI in the Han Chinese population.
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.
