Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fragile X syndrome is the result of transcriptional suppression of the gene FMR1 as a result of a trinucleotide repeat expansion mutation. The normal function of the FMR1 protein (FMRP) and the mechanism by which its absence leads to mental retardation are unknown. Ribonucleoprotein particle (RNP) domains were identified within FMRP, and RNA was shown to bind in stoichiometric ratios, which suggests that there are two RNA binding sites per FMRP molecule. FMRP was able to bind to its own message with high affinity (dissociation constant = 5.7 nM) and interacted with approximately 4 percent of human fetal brain messages. The absence of the normal interaction of FMRP with a subset of RNA molecules might result in the pleiotropic phenotype associated with fragile X syndrome.
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PMID:FMR1 protein: conserved RNP family domains and selective RNA binding. 769 1

Male patients with fragile X syndrome lack FMR1 protein due to silencing of the FMR1 gene by amplification of a CGG repeat and subsequent methylation of the promoter region. The absence of FMR1 protein leads to mental retardation, aberrant behavior, and macroorchidism. Hardly anything is known about the physiological function of FMR1 and the pathological mechanisms leading to these symptoms. Therefore, we designed a knockout model for the fragile X syndrome in mice. The knockout mice lack normal Fmr1 protein and show macroorchidism, learning deficits, and hyperactivity. Consequently, this knockout mouse may serve as a valuable tool in the elucidation of the physiological role of FMR1 and the mechanisms involved in macroorchidism, abnormal behavior, and mental retardation.
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PMID:Fmr1 knockout mice: a model to study fragile X mental retardation. The Dutch-Belgian Fragile X Consortium. 803 9

Fragile X syndrome is the most common cause of inherited mental retardation in humans. The fragile X gene (FMR1) has been cloned and the mutation causing the disease is known. The molecular basis of the disease is an expansion of a trinucleotide repeat sequence (CGG) present in the first exon within the 5' untranslated region of the FMR1 gene. Affected individuals have repeat CGG sequences of above 200. As a result the gene is not producing protein. It has been shown that the FMR1 protein has RNA binding activity, but the function of this RNA binding activity is not known. The timing and mechanism of repeat amplification are not yet understood. An animal model for fragile X syndrome has been generated, which can be used to study the clinical and biochemical abnormalities caused by absence of FMR1 protein product.
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PMID:A fragile gene. 852 88

The fragile X syndrome of mental retardation is one of the most common genetic diseases. The mutation causing this disease was the first of a new class of mutations involving repeat sequences disturbing gene function. Fragile X mutations consist of an expansion of a CGG trinucleotide repeat in the FMR1 gene, which is inactivated as a result of this expansion. The lack of FMR1 protein is believed to be responsible for the mental retardation. The mechanism and the timing of the repeat amplification are still not known. Characterization of the repeat has clarified the genetics of fragile X syndrome, and has given tools to establish the diagnosis and to determine carrier status.
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PMID:Complex behavior of simple repeats: the fragile X syndrome. 855 26

The KH module is a sequence motif found in a number of proteins that are known to be in close association with RNA. Experimental evidence suggests a direct involvement of KH in RNA binding. The human FMR1 protein, which has two KH domains, is associated with fragile X syndrome, the most common inherited cause of mental retardation. Here we present the three-dimensional solution structure of the KH module. The domain consists of a stable beta alpha alpha beta beta alpha fold. On the basis of our results, we suggest a potential surface for RNA binding centered on the loop between the first two helices. Substitution of a well-conserved hydrophobic residue located on the second helix destroys the KH fold; a mutation of this position in FMR1 leads to an aggravated fragile X phenotype.
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PMID:Three-dimensional structure and stability of the KH domain: molecular insights into the fragile X syndrome. 861 76

Fragile X syndrome, the most common form of hereditary mental retardation, usually results from lack of expression of the FMR1 gene. The FMR1 protein is a cytoplasmic RNA-binding protein. The RNA-binding activity of FMR1 is an essential feature of FMR1, as fragile X syndrome can also result from the expression of mutant FMR1 protein that is impaired in RNA binding. Recently, we described two novel cytoplasmic proteins, FXR1 and FXR2, which are both very similar in amino acid sequence to FMR1 and which also interact strongly with FMR1 and with each other. To understand the function of FMR1 and the FXR proteins, we carried out cell fractionation and sedimentation experiments with monoclonal antibodies to these proteins to characterize the complexes they form. Here, we report that the FMR1 and FXR proteins are associated with ribosomes, predominantly with 60S large ribosomal subunits. The FXR proteins are associated with 60S ribosomal subunits even in cells that lack FMR1 and that are derived from a fragile X syndrome patient, indicating that FMR1 is not required for this association. We delineated the regions of FMR1 that mediate its binding to 60S ribosomal subunits and the interactions among the FMR1-FXR family members. Both regions contain sequences predicted to have a high propensity to form coiled coil interactions, and the sequences are highly evolutionarily conserved in this protein family. The association of the FMR1, FXR1, and FXR2 proteins with ribosomes suggests they have functions in translation or mRNA stability.
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PMID:Specific sequences in the fragile X syndrome protein FMR1 and the FXR proteins mediate their binding to 60S ribosomal subunits and the interactions among them. 866

The fragile X syndrome, one of the most common forms of inherited mental retardation, is caused by an expansion of a polymorphic CGG repeat upstream the coding region of the FMR1 gene. These expansions are associated with hypermethylation of the FMR1 gene, which results in the absence of the gene product, the FMR1 protein (FMRP). The physiological function of FMRP remains to be determined. We studied the ultrastructural localization of FMRP at the electron microscopical level using the immunogold technique. FMRP is associated with ribosomes attached to the endoplasmic reticulum and with ribosomes free in the cytoplasm. In addition, FMRP is found in the nucleus where the protein is associated with the granular component of the nucleolus. The cellular function of FMRP is hypothesized in relation to its subcellular distribution.
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PMID:Association of FMRP with ribosomal precursor particles in the nucleolus. 876 90

The fragile X syndrome is the most common inherited cause of mental retardation that is known. The prevalence of mental retardation from this syndrome ranges from 1 in 1,250 to 1 in 4,000 in the general population, although the prevalence of female carriers has been reported to be as high as 1 in 259. The discovery of the FMR1 gene mutation in 1991 has simplified diagnosis, enhanced our understanding of the spectrum of involvement in the fragile X syndrome, and stimulated research regarding the normal function of the FMR1 protein in brain development. Advances have also occurred in the treatment of the fragile X syndrome, and psychopharmacologic and educational interventions are reviewed here.
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PMID:Fragile X syndrome. Molecular and clinical insights and treatment issues. 910 37

Fragile X syndrome is the most frequent cause of heritable mental retardation. Most patients have a mutation in the 5' untranslated region of the FMR1 gene, consisting of the amplification of a polymorphic (CGG)nrepeat sequence, and cytogenetically express the folate-sensitive fragile site FRAXA in Xq27.3. Fragile X patients harbour an expanded sequence with >200 CGG repeats (full mutation), accompanied by methylation of most cytosines of the sequence itself and of the upstream CpG island. This abnormal hypermethylation of the promoter suppresses gene transcription, resulting in the absence of the FMR1 protein. Rare individuals of normal intelligence were shown to carry a completely or partially unmethylated full mutation and to express the FMR1 protein. Given this observation and knowing that the open reading frame of the mutated FMR1 gene is intact, we decided to investigate whether its activity could be restored in vitro by inducing DNA demethylation with 5-azadeoxycytidine (5-azadC) in fragile X patients' lymphoblastoid cells. We report that treatment with 5-azadC causes reactivation of fully mutated FMR1 genes with 300-800 repeats, as shown by the restoration of specific mRNA and protein production. This effect correlates with the extent of promoter demethylation, determined by restriction analysis with methylation-sensitive enzymes. These results confirm the critical role of FMR1 promoter hypermethylation in the pathogenesis of the fragile X syndrome, provide an additional explanation for the normal IQ of the rare males with unmethylated full mutations and pave the way to future attempts at pharmacologically restoring mutant FMR1 gene activity in vivo.
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PMID:In vitro reactivation of the FMR1 gene involved in fragile X syndrome. 938 10

The fragile X syndrome, an X linked mental retardation syndrome, is caused by an expanded CGG repeat in the first exon of the FMR1 gene. In patients with an expanded repeat the FMR1 promoter is methylated and, consequently, the gene is silenced and no FMR1 protein (FMRP) is produced, thus leading to the clinical phenotype. Here we describe a prenatal diagnosis performed in a female from a fragile X family carrying a large premutation. In chorionic villus DNA of the male fetus the normal maternal CGG allele and a normal pattern on Southern blot analysis were found in combination with the FRAXAC2 and DXS297 allele of the maternal at risk haplotype. A second chorionic villus sampling was performed giving identical results on DNA analysis and, in addition, expression of FMRP was shown by immunohistochemistry. We concluded that the male fetus was not affected with the fragile X syndrome. Subsequent detailed haplotype analysis showed a complex recombination pattern resembling either gene conversion or a double crossover within a 20 kb genomic region.
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PMID:Prenatal diagnosis of the fragile X syndrome: loss of mutation owing to a double recombinant or gene conversion event at the FMR1 locus. 939 87


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