Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the function of the FMR1 gene, we applied RNA in situ hybridization to cryosections of mice from different developmental stages. The murine Fmr-1 was found transcribed in a ubiquitous manner with an expression pattern similar to glyceraldehyd phosphate dehydrogenase, Gapdh, which was used as a control gene. A significant difference in the Fmr-1 expression pattern, however, was markedly enhanced expression specifically confined to the testis and the fetal ovary. In the immature and mature testis an elevated level of Fmr-1 expression is found in type A1 spermatogonia. Expression in the testis is observed in fetal life, reaches the highest level in the immature testis, and declines early in adult life. In the mature ovary no specific Fmr-1 expression signal was found but enhanced levels were seen in the fetal ovary. At this developmental stage proliferation of oogonia takes place. It is suggested that FMR1 serves a special function during germ cell proliferation in males and females. These findings are discussed in the light of the current observation that fragile X patients produce only sperm with a premutation sized allele. Two hypotheses are put forward: (1) In males lack of FMR1 function results in a premeiotic defect preventing spermatogonia with a full mutation to reach meiosis. A fragile X mutation can be passed on to offsprings only as a premutation (selection hypothesis). (2) Transition of a premutation allele to full mutation occurs in a postzygotic stage after separation of the germ line and is restricted to soma cells (restriction hypothesis). Expression of FMR1 in proliferating germ cells is in line with both hypothesis.
Hum Mol Genet 1993 Dec
PMID:Enhanced expression of the murine FMR1 gene during germ cell proliferation suggests a special function in both the male and the female gonad. 811 72

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

In the filamentous fungus Podospora anserina, mating type is specified by a single locus with two alternate alleles, termed mat- and mat+. A previous study has shown that the mat+ sequence consists of 3.7 kb and contains a single gene relevant to the sexual cycle. This gene, called FPR1, encodes a protein with a HMG DNA-binding domain and is required for fertilization and for the development of the fertilized fruiting body. The mat- sequence, which is 4.7 kb in length, displays a more complex structure. We present here the characterization of two genes, called SMR1 and SMR2, which are present in the mat- allele along with the FMR1 gene. FMR1, whose role in the sexual cycle has been already partially described, encodes a protein with an alpha 1-domain and was shown to control fertilization. We demonstrate that these three genes are required for the developmental events that occur in the female organ after fertilization. The additional role of FMR1 requires a region of unknown function that is distinct from the alpha 1-domain. SMR1 encodes a protein with a putative acidic/hydrophobic alpha-helix, which has been proposed to be a feature common to transcriptional activators. The protein sequence deduced from SMR2 contains an HMG motif suggesting that it is a transcription factor.
Mol Gen Genet 1993 Dec
PMID:The mat- allele of Podospora anserina contains three regulatory genes required for the development of fertilized female organs. 826 41

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

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

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


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