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The trinucleotide repeat sequences which become unstable in fragile X syndrome and myotonic dystrophy are located in the untranslated regions of their respective genes, FMR1 and DM1. This implies that a functional constraint other than coding capacity maintains the presence of the repeats. In the case of fragile X syndrome, sequences adjacent to the repeat are methylated in affected individuals and the FMR1 gene is transcriptionally inactive. We demonstrate that the fragile X p(CCG)n repeat itself is methylated in vivo and that methylation of this repeat is able to inhibit in vitro binding of a novel, specific nuclear p(CCG)n binding protein (CCG-BP1)--one of at least 10 distinct simple tandem repeat sequence binding proteins (STR-BPs). We describe additional, apparently distinct, binding activities both for the methylated form of the p(CCG)n repeat and for each of the single strands of the repeat.
Hum Mol Genet 1993 Sep
PMID:Fragile X syndrome unstable element, p(CCG)n, and other simple tandem repeat sequences are binding sites for specific nuclear proteins. 824 66

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)
Hum Mol Genet 1993 Oct
PMID:High resolution methylation analysis of the FMR1 gene trinucleotide repeat region in fragile X syndrome. 826 19

The fragile X syndrome is due to a CGG triplet expansion in the first exon of FMR1, resulting in hypermethylation and extinction of gene expression. To further our understanding of the gene's involvement in the syndrome, we report the physical structure of this locus. A high resolution restriction map of the FRAX(A) locus has been prepared encompassing approximately 50 kb. Using exon-exon PCR and restriction analysis, the FMR1 gene has been determined to consist of 17 exons spanning 38 kb of Xq27.3. Each intron-exon boundary has been sequenced. In general, the splice donors and acceptors located in the 5' portion of the gene demonstrate greater adherence to consensus than those in the 3' end, providing a possible explanation for the finding of alternative splicing in FMR1. The elucidation of the exon composition of the FMR1 gene and its flanking region will enhance detection of coding sequence mutations possible in fragile X phenocopy individuals.
Hum Mol Genet 1993 Aug
PMID:Fine structure of the human FMR1 gene. 806 29

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 FMR1 gene, associated with fragile X syndrome, has recently been cloned and the sequence of partial cDNA clones is known. We have determined additional cDNA sequences both at the 5' and 3' end. We have characterized the expressed gene by means of RT-PCR in various tissues and have found that alternative splicing takes place in the FMR1 gene, which does not seem to be tissue specific. When the different alternative splicing events are combined, 12 distinct mRNA products could result from FMR1 expression in each tested tissue. In all these transcripts the open reading frame is maintained until the same stop codon. At the 3' end alternative use of polyadenylation signals is found. The alternative splicing allows functional diversity of the FMR-1 gene. Whether all the possible proteins will be synthesized and whether they will be functionally active has to be determined.
Hum Mol Genet 1993 Apr
PMID:Alternative splicing in the fragile X gene FMR1. 840 31

The fragile X syndrome is associated with an expanding CGG repeat in the 5' untranslated region of the first exon of the FMR1 gene. Subsequent methylation of the promoter region inhibits expression of the FMR1 gene. In two clinically normal brothers large, expanded CGG repeats and cytogenetically visible fragile sites were found. The FMR1 promoter was unmethylated and both RNA and protein could be detected. This indicates that inactivation of the FMR1 gene and not repeat expansion itself results in the fragile X phenotype. We conclude that repeat expansion does not necessarily induce methylation and that methylation is no absolute requirement for the induction of fragile sites.
Hum Mol Genet 1995 Nov
PMID:Normal phenotype in two brothers with a full FMR1 mutation. 858 87

Both sequence length and sequence content are important parameters in determining stability of the fragile X syndrome CGG repeat. In order to estimate the incidence of uninterrupted CGG repeats in the general population and to gain insight into mechanisms responsible for the loss and acquisition of AGG interruptions, 406 randomly selected FMR1 CGG repeat alleles from four broad ethnic groups were assayed for AGG punctuation. Among the 79 different classes of alleles detected, long uninterrupted tracts of pure repeats were rare in the general population, with only 1/406 or 0.25% found at the instability threshold (34-37 pure CGG repeats). There was no significant difference (P>0.05) in the distribution of alleles with long (>20) pure repeat tracts among the different ethnic groups, suggesting that different ethnic groups should be equally susceptible to the development of the disease. Analysis of an additional 43 alleles with total repeat lengths between 35 and 50 repeats, revealed that highly interrupted CGG repeats alleles (>2 AGG interruptions) occur preferentially at modal repeat lengths in the population, providing confirmatory evidence that the presence of AGG interruptions confers stability. A consideration of length variation of the most 3' tract of pure repeats revealed a bimodal distribution pattern with maxima at approximately 10 and 20 repeats. Only unimodal distributions with maxima 9 or 10 were observed for the 5' tract and middle CGG tract within the FMR1 CGG repeat substructure. These results suggest that the loss of the most 3' AGG interruption or its conversion to CGG is a common event in the human population, occurring by a mechanism which preserves overall repeat length. This bias for loss of the distal-most AGG interruption likely plays an important part in predisposing human alleles to the development of the X syndrome.
Hum Mol Genet 1995 Dec
PMID:Population survey of the human FMR1 CGG repeat substructure suggests biased polarity for the loss of AGG interruptions. 863 88

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.
Mol Cell Biol 1996 Jul
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

In order to characterize the dynamics of CGG repeat instability at the fragile X syndrome locus (FMR1 gene), we have used small pool PCR to estimate the mutation rate within germline (sperm) and somatic tissue (leukocytes) of two normal males, one carrying the most common 29 CGG repeats allele, the other carrying a borderline normal-premutated allele of 55 repeats. Large contractions and moderate expansions of the repeat were found in sperm and blood for the 55 repeat allele while almost no variation was found in sperm or blood with the 29 repeat allele. Somatic blood DNA exhibited fewer expansions and contractions than sperm. Contractions were more frequent than expansions, and all the expansions were found in the +4 to +10 repeats range, while most of the contractions were found in the -10 to -30 range, suggesting that a subset of contractions results from a distinct mechanism. These results also suggest that the dynamics of the CGG repeat could be partly due to germline instability within the high normal or premutated ranges.
Hum Mol Genet 1996 Jun
PMID:Analysis of germline variation at the FMR1 CGG repeat shows variation in the normal-premutated borderline range. 877 98

Fragile X syndrome is a frequent cause of mental retardation resulting from the absence of FMRP, the protein encoded by the FMR1 gene. FMRP is an RNA-binding protein of unknown function which is associated with ribosomes. To gain insight into FMRP function, we performed immunolocalization analysis of FMRP truncation and fusion constructs which revealed a nuclear localization signal (NLS) in the amino terminus of FMRP as well as a nuclear export signal (NES) encoded by exon 14. A 17 amino acid peptide containing the FMRP NES, which closely resembles the NES motifs recently described for HIV-1 Rev and PKI, is sufficient to direct nuclear export of a microinjected protein conjugate. Sucrose gradient analysis shows that FMRP ribosome association is RNA-dependent and FMRP is found in ribonucleoprotein (RNP) particles following EDTA treatment. These data are consistent with nascent FMRP entering the nucleus to assemble into mRNP particles prior to export back into the cytoplasm and suggests that fragile X syndrome may result from altered translation of transcripts which normally bind to FMRP.
Hum Mol Genet 1996 Aug
PMID:The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals. 884 25


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