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Query: UNIPROT:P06889 (Mol)
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A new fragile site (FRAXE) in Xq28 is described. It appears to be a typical folate sensitive fragile site. The fragile site is not associated with mental retardation, it does not give abnormal results when subjected to Southern analysis with probe pfxa3 which detects the unstable DNA sequence characteristic of fragile X syndrome. In situ hybridization mapping locates the fragile site between 150 kb and 600 kb distal to FRAXA. The distinction between the two fragile sites is important clinically since cytogenetic detection of FRAXE, without molecular analysis, could result in misdiagnosis of fragile X syndrome.
Hum Mol Genet 1992 May
PMID:Characterisation of a new rare fragile site easily confused with the fragile X. 130 Nov 46

Three fragile sites, FRAXA, FRAXE and FRAXF lie in the Xq27-28 region of the human X chromosome. The expression of FRAXA is associated with the fragile X syndrome, the most prevalent form of inherited mental retardation whilst the expression of FRAXE is associated with a rarer and comparatively milder form of mental handicap. Both the FRAXA and FRAXE sites have been cloned and the fragile site expression found to be due to the expansion of analogous CGG/GCC trinucleotide repeat arrays. We describe here the cloning of the third fragile site, FRAXF, and demonstrate that it involves the expansion of a (GCCGTC)n(GCC)n compound array. PCR analyses across the repeat of normal individuals show that the number of triplets in the array ranges from 12-26 and the most common allele consists of 14 triplet units. Sequencing analyses show that 95% of normal individuals have three copies of the GCCGTC motif and in these individuals, the size variation observed by PCR is due to copy number alterations in the GCC array. In a cytogenetically positive male with developmental delay, the array is expanded by > 900 triplets and the adjacent CpG-rich region is methylated. The array is also expanded in cytogenetically positive carrier females from the family originally used to define the FRAXF site. We conclude that the expanded array corresponds to the FRAXF fragile site.
Hum Mol Genet 1994 Dec
PMID:The cloning of FRAXF: trinucleotide repeat expansion and methylation at a third fragile site in distal Xqter. 788 7

We report the case of a mentally normal male carrier of a fragile X full mutation with a 'methylation mosaic' hybridization pattern, who carried premutation-size mutations in his sperm cells and transmitted one of them to a daughter. Clinical evaluation of the father revealed a phenotype resembling that of the fragile X syndrome but without mental impairment and 4% fragile sites on cytogenetic analysis. Direct FRAXA genotyping revealed 40% abnormal methylation at the classical EagI FMR-1 restriction site, a delta of 400 bp to 1400 bp associated, in the non-methylated region, to a widely spread smear. This is thus a rare occurrence of a male carrier of a fragile X full mutation with significant methylation of the EagI site and no mental impairment. A premutation of 400 bp was detected in his daughter's leukocytes and analysis of sperm cells from the father revealed a normal spermogram and only 400 bp premutations. This is the first documented case of transmission (with analysis of sperm DNA) of a fragile X mutation from a male carrier of a full fragile X mutation to a girl. This may be due to the early setting apart of progenitor germ cells in males having inherited a premutation from their mother. It is more likely that there could be a strong selection process favouring those cells with a reverted full mutation which produced a small and unmethylated FMR-1 CpG island allowing for re-expression of the FMR-1 gene, especially in male germ cells.
Hum Mol Genet 1994 Jun
PMID:No mental retardation in a man with 40% abnormal methylation at the FMR-1 locus and transmission of sperm cell mutations as premutations. 795 Dec 39

A number of recent studies have found non-random association between the fragile X mutation and genotypes for the closest-linked flanking markers, suggesting either a limited number of 'founder' mutations or, alternatively, a predisposing haplotype for the fragile X expansions. Using three microsatellite markers within 150 kb of FRAXA, we have compared haplotypes in a series of fragile X males and in a control population and find a markedly different distribution in the two samples, with apparently greater haplotype diversity in the fragile X sample. In the control sample, various non-random associations of CGG repeat numbers with flanking haplotypes were recorded which provide a clue to the likely origins of the fragile X mutation, suggesting more than one mechanism for the initial expansion event.
Hum Mol Genet 1994 Mar
PMID:Insert size and flanking haplotype in fragile X and normal populations: possible multiple origins for the fragile X mutation. 801 51

The recent observation that the mutation underlying a number of genetic diseases including fragile sites, FRAXA and FRAXE (associated with mental retardation), myotonic dystrophy, spinal and bulbar muscular atrophy (Kennedy's disease), Huntington's disease and spinocerebellar ataxia type 1 are caused by the expansion of a trinucleotide repeat sequence will lead to interest in the identification of such sequences in regions related to other diseases. We report here the identification of all ten classes of trinucleotide repeats within a 2 Mbp region of 4p16.3 containing the Huntington's disease (HD) gene. Fifty one triplet repeats were identified and localised on a high resolution restriction map of a cosmid contig covering this region. This included the triplet repeat (CAG)n, which has subsequently been shown to be expanded in Huntington's disease patients.
Hum Mol Genet 1994 Jan
PMID:Distribution of trinucleotide repeat sequences across a 2 Mbp region containing the Huntington's disease gene. 816 55

FRAXA is unique amongst fragile sites in that it is intimately involved with a specific clinical phenotype, the fragile X syndrome. Whilst the majority of fragile X individuals have been found to have a characteristic mutation in the FMR1 gene, a small proportion of individuals exhibiting fragility have no such mutation. Investigation of the site of chromosome fragility in these FMR1 mutation negative, fragile X site positive individuals, has identified a second site of fragility, FRAXE. However, the presence of FRAXE has not explained all such cases. Here we describe a fragile X site positive, FMR1 mutation negative family, in which chromosome fragility is not due to the FRAXA or FRAXE but is due to a third site designated FRAXF. Using fluorescent in situ hybridisation (FISH) this site is shown to lie over 1Mb distal to FRAXA. The identification of a third fragile site in this small region of the X chromosome provides an opportunity to extend our studies of the molecular nature of chromosome fragility.
Hum Mol Genet 1993 Feb
PMID:The identification of a third fragile site, FRAXF, in Xq27--q28 distal to both FRAXA and FRAXE. 849 7

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.
Biochem Mol Med 1995 Oct
PMID:Frequency of FMR1 premutations in a consecutive newborn population by PCR screening of Guthrie blood spots. 859 39

We have recently reported results of DNA replication analysis of three X-linked loci (FRAXA, F8C and XIST) on the X chromosomes in male and female fibroblasts using fluorescence in situ hybridization (FISH) (1). Although our findings that XIST replicates later on the active X than on the inactive X are similar to those of Boggs & Chinault (2) based on a FISH assay in female lymphoblasts, they are the opposite of observations recently reported by Hansen et al. (3) using a different technique. Because our conclusions about the inactive X were deduced from the behavior of the active X in male cells, we reexamined the time when these loci replicate on the human inactive X chromosome isolated from its homolog in somatic cell hybrids. We also studied the same chromosome as an active X in related hybrids. The results provide direct evidence that the expressed XIST locus on the inactive X replicates earlier than its repressed homolog on the active X and earlier than the FRAXA locus which is repressed on this chromosome. The silent XIST locus on the active X replicates late along with F8C which is also not transcribed in these cells. Possible reasons for the different results obtained by Hansen et al. (3) are discussed.
Somat Cell Mol Genet 1995 Sep
PMID:The XIST locus replicates late on the active X, and earlier on the inactive X based on FISH DNA replication analysis of somatic cell hybrids. 861 29

Preliminary results on a large population-based molecular survey of FRAXA and FRAXE are reported. All boys with unexplained learning difficulties are eligible for inclusion in the study and data are presented on the first 1013 tested. Individuals were tested for the number of trinucleotide repeats at FRAXA and FRAXE and typed for four flanking microsatellite markers. Mothers of 760 boys were tested to determine the stability of the FRAXA and FRAXE repeats during transmission and to provide a population of control chromosomes. The frequency of FRAXA full mutations was 0.5%, which gives a population frequency of 1 in 4994, considerably less than previous reports suggest. No FRAXE full mutations were detected, confirming the rarity of this mutation. In the boys' X chromosomes, we detected one FRAXA premutation with 152 repeats and one putative FRAXE premutation of 87 repeats. No full or premutations were seen in the control chromosomes. A significant excess of intermediate alleles at both FRAXA and FRAXE was detected in the boys' X chromosomes by comparison with the maternal control chromosomes. This suggests that relatively large unmethylated repeats of sizes 41-60 for FRAXA and 31-60 for FRAXE may play some role in mental impairment. No instability was found in transmissions of minimal or common alleles in either FRAXA or FRAXE, but we saw two possible instabilities in transmission of FRAXA and two definite instabilities in transmission of FRAXE among 43 meioses involving intermediate or premutation sized alleles. We found no linkage disequilibrium between FRAXA and FRAXE but did find significant linkage disequilibrium between large alleles at FRAXE and allele 3 at the polymorphic locus DXS1691 situated 5 kb distal to FRAXE.
Hum Mol Genet 1996 Jun
PMID:Population screening at the FRAXA and FRAXE loci: molecular analyses of boys with learning difficulties and their mothers. 877 86

The rare folate-sensitive, fragile sites on chromsomes X, 11, and 16 contain blocks of CCG triplet repeats and large expansions of the CCG block at the FRAXA site produce the fragile X syndrome (FraX). The fragile, poorly staining nature of these sites suggested an altered chromatin structure. Here, repeating CCG DNAs from FraX patients were tested for their ability to assemble into nucleosomes, the basic subunits of chromatin, using in vitro nucleosome reconstitution, electron microscopy and competitive assembly gel retardation assays. CCG blocks of >50 repeats displayed strong nucleosome exclusion, providing a possible explanation for the nature of these sites.
J Mol Biol 1996 Nov 08
PMID:Long CCG triplet repeat blocks exclude nucleosomes: a possible mechanism for the nature of fragile sites in chromosomes. 891 33


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