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 mental retardation syndrome is associated with an expansion of a CGG repeat within the 5'UTR of the first exon of the FMR1 gene, abnormal methylation of the CpG island in the promoter region, and a transcriptional silencing of this gene. We studied transcriptional regulation of the FMR1 gene using protein footprint analysis of the active and inactive gene in vivo . We identified four footprints within the FMR1 promoter region which correspond to consensus binding sites of known transcription factors, alpha-PAL/NRF1, Sp1, H4TF1/Sp1-like and c-myc. These footprints were present in normal cells with a transcriptionally active FMR1 gene. The same footprints were present in different cell types: primary fibroblasts, lymphoblastoid cells and peripheral lymphocytes. However, for the 1.1 kb region analyzed, no footprints were detected in a variety of cell types derived from patients with fragile X syndrome which have a transcriptionally inactive FMR1 gene. A BLAST nucleotide search identified sequence similarities between the region of the FMR1 gene containing the footprints and an analogous region within the promoter region of the gene for the heterogeneous nuclear ribonucleoprotein (hnRNP) A2, a member of a family of ribonucleoproteins implicated in mRNA processing and nuclear-cytoplasm transport. The nucleotide sequences identified in the hnRNP-A2 promoter region correspond to the same consensus binding sites showing DNA-protein interactions in the FMR1 gene. Our previous functional studies and the studies of others demonstrate that FMR proteins, like hnRNP-A2, are also ribonucleoproteins which appear to be involved in mRNA transport. The results from our footprint studies suggest that the expression of the FMR1 gene is regulated by the binding of specific transcription factors to sequence elements in the 5' region of the gene and that this expression may be regulated by elements in common with the hnRNP-A2 gene. Common regulation of these two genes might play an important role in the cooperative processing and transport of mRNA from the nucleus to the translation machinery.
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PMID:Structural and functional characterization of the human FMR1 promoter reveals similarities with the hnRNP-A2 promoter region. 932 68

Fragile X syndrome is the most common inherited form of familial mental retardation. It results from a (CGG)n trinucleotide expansion in the FMR1 gene leading to the typical Martin-Bell phenotype. Clinical features vary depending on age and sex. Expansion of a (CCG)n repeat in the FMR2 gene corresponds to the FRAXE fragile site which lies distal to FRAXA and is also associated with mental retardation, but it is less frequent and lacks a consistent phenotype. Analysis of repeat expansions in these two genes allows the molecular diagnosis of these different entities. We report here the screening of the FRAXA and FRAXE mutations in 222 unrelated mentally retarded individuals attending Spanish special schools. PCR and/or Southern blotting methods were used. We detected full mutations in the FMR1 gene in 11 boys (4.9%) and 1 boy (0.5%) with a CCG repeat expansion in the FMR2 gene. The latter shows mild mental retardation with psychotic behaviour and no remarkable physical traits. Molecular studies revealed a mosaicism for methylation in the FMR2 gene. This case supports the observation that expansions greater than 100 repeats can be partially methylated and cause the phenotype.
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PMID:Screening for FMR1 and FMR2 mutations in 222 individuals from Spanish special schools: identification of a case of FRAXE-associated mental retardation. 934 61

The fragile X syndrome phenotype of mental retardation is almost always caused by abnormal CGG trinucleotide amplification within the FMR1 gene. Occasionally fragile X syndrome results from point mutations or deletions within or around the FMR1 locus. We have identified a mentally retarded African American male with typical fragile X phenotype and a 300-400 base pair intragenic deletion near the CGG repeat segment, present in his peripheral blood lymphocytes with no apparent mosaicism. His mother, who is not retarded, has a full FMR1 CGG expansion mutation with 700-900 repeats. A review of 23 published cases with FMR1 gene deletions shows full FMR1 mutation in the mother of only 1 other propositus, a male with FMR1 full mutation/premutation/deletion mosaicism of his cultured skin fibroblasts and peripheral blood lymphocytes. The various deletions within FMR1 and their clinical significance are reviewed.
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PMID:Fragile X syndrome and deletions in FMR1: new case and review of the literature. 937 26

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 is an X linked, semidominant mental retardation disorder caused by the amplification of a CGG repeat in the 5' UTR of the FMR1 gene. Nineteen fragile X families in which the mutated FMR1 gene segregated were evaluated. The implications of the diagnosis for the parents and family were studied through pedigree information, interviews, and questionnaires. Information about the heredity of fragile X syndrome was only disseminated by family members to a third (124/366) of the relatives with an a priori risk of being a carrier of the fragile X syndrome. Twenty-six percent (94/366) of the relatives were tested. Transmission of information among first degree relatives seemed satisfactory but dropped off sharply with increasing distance of the genetic relationship, leaving 66% uninformed. This is particularly disadvantageous in an X linked disease. Of those subjects tested, 42% (39/94) had a premutation and 18% (17/94) had a full mutation. On average, in each family one new fragile X patient and two new carriers were found. When people have the task of transmitting genetic information to their relatives, they usually feel responsible and capable; however, reduced acquaintance and contact with more distant relative severely reduces the effectiveness of such transfer of information in fragile X families.
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PMID:DNA testing for fragile X syndrome: implications for parents and family. 939 84

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

Fragile X syndrome is an X-linked mental retardation condition that usually is due to a trinucleotide-repeat expansion in the FMR1 gene. Whereas full-mutation alleles (> 230 repeats) lead to fragile X syndrome, premutation alleles (approximately 60-200 repeats) are apparently non-penetrant. However, previous studies have suggested that female premutation carriers may have an increased incidence of premature menopause. To test this possible association, we screened for premutation alleles among 216 women with early menopause (at age < 47 years), 33 of whom had premature menopause (at age < 40 years), as well as among 107 control women, all of whom were ascertained solely on the basis of age at menopause. No full-mutation alleles were found; and only one premutation allele was found, but, it was in a member of the control group. These results are consistent with what would be expected on the basis of chance only. Our sample size was sufficient to rule out a > or = 3-fold increased risk of early menopause and a > or = 9-fold increased risk of premature menopause due to an FMR1 premutation, under a model considering the risk of both sporadic and familial early menopause. Likewise, our results rule out a > or = 4-fold increased risk of familial early menopause and a > or = 26-fold increased risk of familial premature menopause, under a less probable model in which only familial early menopause is considered. These results indicate that the fragile X premutation is not a major risk factor for early menopause and suggest that the risk of premature menopause to fragile X-premutation carriers may not be as great as that reported elsewhere.
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PMID:Fragile X premutations are not a major cause of early menopause. 939 5

The prevalence of the fragile X mental retardation (FMR) 1 and FMR2 full mutations (fM) was examined among 1014 school-age children with academic difficulties but without mental retardation. Both Southern blot and polymerase chain reaction analyses for FMR1 and FMR2 were performed on samples obtained from these children. No fM genes were found, and one FMR1 premutation was identified. The distribution of allele sizes for both genes was comparable to those reported for other clinical and normal population samples. These results suggest that neither the FMR1 nor the FMR2 mutation is a common etiology of academic failure among school-age children without mental retardation and that the prevalence of the FMR1 premutation is no more frequent in children with academic failure than it is in the general population.
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PMID:The FMR1 and FMR2 mutations are not common etiologies of academic difficulty among school-age children. 943 1

The rat androgen-binding protein/sex hormone-binding globulin (ABP/SHBG) gene is regulated by promoters P1 and PA. P1 regulates the mRNA encoding secreted ABP/SHBG, whereas PA regulates an alternate mRNA which encodes a modified protein that is targeted to the nucleus. Promoter PA is GC rich, consisting of 70-80% GC residues. During routine BLAST sequence analysis it was discovered that this GC-rich region is highly related to the human fragile X-related protein 2 (FXR-2) 5'-untranslated RNA sequence. Furthermore, the nucleotide coding sequence of the initial 14 FXR-2 amino acid residues was identical in the ABP/SHBG gene. The 5'-untranslated FXR-2 sequence contains triplet (CGG) repeats, which are also present in the rat ABP/SHBG gene. The meiotic instability of CGG repeats in the human fragile X (FMR1) gene causes the fragile X mental retardation syndrome. The data presented here suggest that the ABP/SHBG and FXR-2 genes overlap with each gene transcribed in the opposite direction. In support of this structure, the human ABP/SHBG and the FXR-2 genes map to the same site on chromosome 17. Thus, the ABP/SHBG gene contains triplet repeats in the alternate promoter PA. It will be of particular interest to determine if triplet instability affects ABP/SHBG gene expression. A triplet instability in the X-linked androgen receptor gene causes spinal and bulbar muscular atrophy.
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PMID:The rat androgen-binding protein (ABP/SHBG) gene contains triplet repeats similar to unstable triplets: evidence that the ABP/SHBG and the fragile X-related 2 genes overlap. 943 88

Fragile X syndrome is the most frequent form of inherited mental retardation and it is caused by deficiency of FMRP, the protein encoded by the FMR1 gene. FMRP is a RNA binding protein of unknown function which is associated with ribosomes. FMRP is found in the cytoplasm, but it is endowed with a nuclear export signal (NES), encoded by exon 14, and a nuclear localization signal (NLS). Characterization of the FMRP NES and NLS domains is presented here. We show by site-directed mutagenesis that three leucine residues in exon 14 are functionally important for the cytoplasmic localization of FMRP. Changing these leucines to serine resulted in a nuclear localization, while another nonconservative change (leucine to tyrosine) did not show such an effect. We also show that the NLS activity is localized between residues 115 and 150, a region that lacks stretches of basic residues. Such stretches are typical of nuclear localization signals that act through the important alpha pathway. The region between residues 151 and 196 can reinforce the NLS activity. A truncated construct containing the N-terminal region of FMRP (residues 1-114) is strikingly concentrated in the nucleus. This suggests that it may contain a domain of strong affinity with a nuclear component.
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PMID:Analysis of domains affecting intracellular localization of the FMRP protein. 944 Jan 21


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