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)

The fragile X mental retardation syndrome is caused by the expansion of an unstable CGG repeat in a 5' exon of the FMR1 gene. Significant linkage disequilibrium between this mutation and flanking microsatellite markers has been observed previously in Caucasian populations, a very unusual finding for an X-linked disease which severely impairs reproduction fitness in affected males. This reflects the multistep process at the origin of the full mutation. We have analyzed the FRAXAC2 and DXS548 microsatellites in 26 fragile X families originating from various parts of Finland, and report a striking founder effect much stronger than the linkage disequilibrium observed previously in other more heterogeneous populations. One DXS548 allele was present on 92% of fragile X chromosomes and on 17% of normal chromosomes. A single haplotype accounted for 73% of fragile X chromosomes, and was found only once in 34 normal chromosomes, corresponding to a relative risk of about 90 compared to its absence. The broad geographic origin of the high-risk haplotype and its expected frequency suggest that it was present in initial settlers of Finland, and could thus have been carried silently through 100 generations.
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PMID:Striking founder effect for the fragile X syndrome in Finland. 804 45

The KH domain is an evolutionarily conserved sequence motif present in many RNA-binding proteins, including the pre-mRNA-binding (hnRNP) K protein and the fragile X mental retardation gene product (FMR1). We assessed the role of KH domains in RNA binding by mutagenesis of KH domains in hnRNP K and FMR1. Conserved residues of all three hnRNP K KH domains are required for its wild-type RNA binding. Interestingly, while fragile X syndrome is usually caused by lack of FMR1 expression, a previously reported mutation in a highly conserved residue of one of its two KH domains (Ile-304-->Asn) also results in mental retardation. We found that the binding of this mutant protein to RNA is severely impaired. These results demonstrate an essential role for KH domains in RNA binding. Furthermore, they strengthen the connection between fragile X syndrome and loss of the RNA binding activity of FMR1.
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PMID:Essential role for KH domains in RNA binding: impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile X syndrome. 815 95

The fragile X mental retardation syndrome is associated with the expansion of trinucleotide 5'-d(CGG)-3' repeats within the FMR1 gene and with hypermethylation of the cytosine residues of these repeats. The expansion and hypermethylation may account for the suppression of the transcription of the FMR1 gene and for the delay of its replication during the cell cycle. Here we show that d(CGG)n oligomers can form a stable Hoogsteen-bonded structure that exhibits properties consistent with those of tetraplex DNA. Oligomers, d(mCGG)n, (n = 4, 5, or 7), at pH 8.0 and in the presence of an alkali metal ion form stable species exhibiting a reduced electrophoretic mobility in nondenaturing polyacrylamide gels. These species are denatured by heating at 90 degrees C for 10 min. With a short d(mCGG)5 oligomer, the slowly migrating species is formed only when the cytosine residue is 5-methylated, whereas with the longer d(CGG)7 it is generated whether or not cytosine is 5-methylated. By contrast, complementary cytosine-rich oligomers do not form analogous complexes. The second-order association kinetics of the formation of the slowly migrating species of d(mCGG)5 suggests that it is an interstrand complex. Formation of intermediate-size complexes between d(mCGG)5 and d(mCGG)7 indicates that the stoichiometry of the slowly migrating structures is tetramolecular. Protection of the complex from methylation by dimethyl sulfate indicates the involvement of the N-7 positions of the guanine residues in Hoogsteen hydrogen bonding, a characteristic of quadruplex structures. If formed in vivo along the expanded and hypermethylated d(mCGG)n stretch, this tetraplex structure could suppress transcription and replication of the FMR1 gene in the fragile X syndrome cells.
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PMID:The fragile X syndrome d(CGG)n nucleotide repeats form a stable tetrahelical structure. 819 63

Fragile X syndrome is the most common form of inherited mental retardation in man. The disease is associated with expansion in the number of tandem CGG trinucleotide repeats in the 5' untranslated region of the human FMR1 gene. Transmitting males, individuals who are unaffected carriers of the disease, show a moderate increase in the number of repeat units, while fully penetrant males show a major expansion in repeat number. Major expansion of the repeat in affected males is correlated with methylation of certain restriction enzyme recognition sites in the 5' CpG island containing the trinucleotide repeat in these patients. Phenotypic expression of the mutation appears to be due to transcriptional silencing of the FMR1 gene. We now report direct high resolution methylation analysis of the trinucleotide repeat and its flanking regions using ligation-mediated PCR genomic sequencing. We find the cytosine residue of all CpG dinucleotides examined within and surrounding the FMR1 trinucleotide repeat to be unmethylated in the DNA of normal male leukocytes and transmitting male lymphoblasts; these same cytosines are methylated in affected male lymphoblasts, in a somatic cell hybrid containing a fragile X chromosome from an affected male, and in a somatic cell hybrid containing a normal inactive X chromosome. The methylation pattern of the FMR1 5' CpG island in affected patients as determined by genomic sequencing is remarkably similar to that seen for the X-linked human phosphoglycerate kinase and hypoxanthine phosphoribosyltransferase gene 5' CpG islands on the inactive human X chromosome.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:High resolution methylation analysis of the FMR1 gene trinucleotide repeat region in fragile X syndrome. 826 19

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 form of mental retardation is presently recognized as the most frequent hereditable cause of mental impairment. The estimated frequency among males is 1 in 1250, and 1 in 2000 among females. Beside mental impairment and behavioural disturbance with hyperactivity and autistic features, the patients are characterized by morphological anomalies, such as an oblong face, broad, rectangular chin, large protruding ears and macro-orchidism. A less severe clinical expression can be found among females heterozygotes of the disorder, manifesting mainly as learning disability. The disorder is associated with the expression of a fragile site at Xq27.3 under conditions of folate depletion in the chromosome culture medium. The molecular mechanism is based on the expansion of a trinucleotide repeat [CCG]n in the promoter region of the FMR1 gene resulting in methylation of the gene. The trinucleotide repeat shows variable lengths of 6 to 53 repeats in the general population, 60 to 200 repeats in carriers of a premutation and over 200 repeats in patients with fragile X syndrome.
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PMID:[Fragile X syndrome: clinical and molecular genetics correlations]. 853 51

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

Fragile X syndrome is the major cause of inherited mental retardation. The molecular basis for the expression of the fragile X phenotype is the expansion of an unstable CGG repeat element which inhibits transcription of the FMR1 gene. The fragile X syndrome shows great diversity in its phenotype as well as in its cytogenetic and molecular status. We have studied, in a large fragile X family, the correlation between the molecular data and the phenotypic expression of the syndrome. We report two brothers who carry identical unmethylated premutated alleles but present different clinical phenotypes. We also suggest that reductions in allele size from one generation to another may be, as in other diseases, because of triplet amplifications, more common at the FRAXA locus than previously thought.
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PMID:Instability of the CGG repeat at the FRAXA locus and variable phenotypic expression in a large fragile X pedigree. 859 40

The fragile X(A) or FRAXA syndrome is the most common form of familial mental retardation and is associated with a fragile site at Xq27.3. The gene responsible for the FRAXA syndrome, the FMR1 gene, has been cloned. inactivation of the FMR1 gene is associated with amplification of a trinucle-otide CGG repeat sequence and methylation of an adjacent CpG island. Previous estimates for the prevalence of the FRAXA syndrome have been based on indirect methods of chromosome analysis in institutions and community workshops for the mentally handicapped. We have analyzed the frequency of premutations of the FMR1 gene in 3002 X chromosomes of 1000 male and 1000 female consecutive newborn nonautoclaved blood spots in an anonymous, unlinked survey. The CGG repeat sizes were calculated by measuring the length of products of the PCR reaction based on the molecular size of labeled markers in a denaturing sequencing gel assay. For consistent PCR amplification a DNA microextraction was necessary, including a phenol/chloroform series. In our population, the CGG allele ranged from 9 to 106 repeats: 97% of alleles had fewer than 40 repeats. The most frequent allele was a repeat of 28. Approximately 2.3% of alleles had CGG repeats ranging from 4 to 49 and 0.37% of alleles had repeats ranging from 50 to 59. The frequency of alleles > 60 repeats in the Manitoba male population is approximately 0.13%. The use of nonautoclaved Guthrie blood spots for population screening of FRAXA premutations is not recommended. The necessity of a phenol/chloroform DNA microextraction is tedious and time consuming. The low yield of DNA (250 ng) does not allow for reanalysis by Southern of apparently homozygous females with potentially unstable CGG alleles in the 40-60 repeat range and likely underestimates premutation carrier status.
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PMID:Frequency of FMR1 premutations in a consecutive newborn population by PCR screening of Guthrie blood spots. 859 39

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


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