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

The fragile-X syndrome of mental retardation is associated with an expansion in the number of CGG repeats present in the FMR1 gene. The repeat region is within sequences characteristic of a CpG island. Methylation of CpG dinucleotides that are 5' to the CGG repeat has been shown to occur on the inactive X chromosome of normal females and on the X chromosome of affected fragile-X males, and is correlated with silencing of the FMR1 gene. The methylation status of CpG sites 3' to the repeat and within the repeat itself has not previously been reported. We have used two methylation-sensitive restriction enzymes, AciI and Fnu4HI, to further characterize the methylation pattern of the FMR1 CpG island in normal individuals and in those carrying fragile-X mutations. Our results indicate that: (i) CpG dinucleotides on the 3' side of the CGG repeat are part of the CpG island that is methylated during inactivation of a normal X chromosome in females; (ii) the CGG repeats are also part of the CpG island and are extensively methylated as a result of normal X-chromosome inactivation; (iii) similar to normal males, unaffected fragile-X males with small CGG expansions are unmethylated in the CpG island; for affected males, the patterns of methylation are similar to those of a normal, inactive X chromosome; (iv) in contrast to the partial methylation observed for certain sites in lymphocyte DNA, complete methylation was observed in DNA from cell lines containing either a normal inactive X chromosome or a fragile-X chromosome from an affected male.(ABSTRACT TRUNCATED AT 250 WORDS)
Hum Mol Genet 1992 Nov
PMID:Methylation analysis of CGG sites in the CpG island of the human FMR1 gene. 130 Nov 65

The two idiomorphic alleles called mat+ and mat-, which control the mating types in Podospora anserina, have been cloned. Mat+ and mat- encompass 3.8 kb and 4.7 kb respectively, of unrelated DNA sequences flanked by common sequences. Subcloning allowed the identification and localization in each locus of the gene that controls fertilization, probably by determining the mating type. The mat+ gene, called FPR1, encodes a protein with a potential DNA-binding HMG domain. The presence of this motif suggests that the FPR1 polypeptide may act as a transcriptional factor. The mat- gene called FMR1 encodes a protein containing a motif that is also found in proteins controlling mating functions in Saccharomyces cerevisiae and Neurospora crassa. The role of this motif has not yet been established. Unlike the mat+ locus, where the FPR1 gene seems to represent the major information, the mat- locus contains information necessary for the post-fertilization steps of the sexual cycle besides the FMR1 gene.
Mol Gen Genet 1992 May
PMID:The mating types of Podospora anserina: functional analysis and sequence of the fertilization domains. 153 66

The fragile X syndrome is an X-linked inherited disease and is the result of transcriptional inactivation of the FMR1 gene and the absence of its encoded FMR protein (FMRP). Using a specific monoclonal antibody directed against human FMRP, we have studied the steady-state levels of its murine homolog in several tissues and organs of adult and young mice. In immunoblot analyses, the antibody recognizes a heterogeneous subset of proteins with apparent molecular weights ranging from 80 to 70 kDa. These proteins are detected in all the 27 tissues tested; however, the relative proportion of each polypeptide recognized varies between tissues, and a significantly higher expression is observed in young animals. Northern blot analysis of RNA extracted from selected tissues from adult mouse shows that these tissues express the major 4.8 kb mRNA, although at different levels, and contain several additional shorter transcripts, particularly in muscular tissues. We also report that expression of the FMR1 gene is modulated in proliferating and quiescent primary mouse kidney cell cultures with an inverse relationship between levels of FMR1 mRNA and of its encoded proteins. This suggests that FMRPs are highly stable in quiescent cells and that FMR1 expression is likely post-transcriptionally controlled. Our results document the widespread expression of the FMR1 gene, and suggest that it is controlled by different mechanisms implicated in cell growth and differentiation.
Hum Mol Genet 1995 May
PMID:A heterogeneous set of FMR1 proteins is widely distributed in mouse tissues and is modulated in cell culture. 763 36

FMR1 protein expression was studied in different tissues. In human, monkey and murine tissues, high molecular mass FMR1 proteins (67-80 kDa) are found, as shown in lymphoblastoid cells lines. The identity of these proteins was confirmed by their absence in tissues from patients with the fragile X syndrome and a FMR1 knock-out mouse. An Ile367Asn substitution in the FMR1 protein did not alter the translation, processing and localization of FMR1 proteins in lymphoblastoid cells from a patient carrying this mutation. All the high molecular mass FMR1 proteins isolated from normal lymphoblastoid cells and cells from the patient with the Ile367Asn substitution were able to bind RNA. However, the FMR1 proteins of the patient had reduced affinity for RNA binding at high salt concentrations. In some human, monkey and murine tissues low molecular mass FMR1 proteins (39-41 kDa) were found, which had the same N terminus as the 67-90 kDa isoforms, but differ in their C terminus and are therefore most likely the result of carboxy-terminal proteolytic cleavage. These low molecular mass FMR1 proteins did not bind RNA, in contrast with the high molecular mass FMR1 proteins. The significance of these low molecular mass proteins remains to be studied.
Hum Mol Genet 1995 May
PMID:Characterization of FMR1 proteins isolated from different tissues. 763 50

The fragile X syndrome is the most frequent cause of inherited mental retardation. The molecular mechanism of the disorder is based on the expansion of a CGG repeat in the 5' UTR of the FMR1 gene in the majority of fragile X patients. The instability of this CGG repeat containing region is not restricted to the CGG repeat itself but expands to the flanking region as well. We describe four unrelated fragile X patients that are mosaic for both a full mutation and a small deletion in the CGG repeat containing region. Sequence analysis of the regions surrounding the deletions showed that both the (CGG)n repeat and some flanking sequences were missing in all four patients. The 5' breakpoints of the deletions were found to be located between 75-53 bp proximal to the CGG repeat. This suggests the presence of a hot spot region for deletions in the CGG repeat region of the FMR1 gene and emphasizes the instability of this region in the presence of an expanded CGG repeat.
Hum Mol Genet 1995 Jan
PMID:Hotspot for deletions in the CGG repeat region of FMR1 in fragile X patients. 771 33

Fragile X syndrome is one of the most common genetic causes of mental retardation, yet the mechanisms controlling expression of the fragile X mental retardation gene FMR1 are poorly understood. To identify sequences regulating FMR1 transcription, transgenic mouse lines were established using a fusion gene consisting of an E.coli beta-galactosidase reporter gene (lacZ) linked to a 2.8 kb fragment spanning the 5'-region of FMR1. Five transgenic mouse lines showed lacZ expression in brain, in particular in neurons of the hippocampus and the granular layer of the cerebellum. Expression of the reporter gene was also detected in Leydig cells and spermatogonia in the testis, in many epithelia of adult mice, and in the two other steroidogenic cell types, adrenal cortex cells and ovarian follicle cells. Embryonic tissues which showed strong activity of the reporter gene included the telencephalon, the genital ridge, and the notochord. This expression pattern closely resembles the endogenous one, indicating that the 5' FMR1 gene promoter region used in this study contains most cis-acting elements regulating FMR1 transcription.
Hum Mol Genet 1995 Mar
PMID:Tissue-specific expression of a FMR1/beta-galactosidase fusion gene in transgenic mice. 779 88

To determine factors governing triplet repeat expansion at FMR1, we need to understand the basis of normal variation. We have sequenced the FMR1 repeat from 102 normal X chromosomes and show that most are interrupted with a regularly spaced AGG trinucleotide giving an ordered structure to the array. Five types of arrays were identified consisting of varying numbers of a core unit with consensus [AGG(CGG)9]. Additional variation in the length of the (CGG)n portion within each unit generates the continuum of lengths seen on normal chromosomes. Ten per cent contain long, uninterrupted tracts of (CGG)n, and their lengths suggest they have arisen by the loss of AGG triplets from longer interrupted arrays. Haplotype analysis of arrays carrying long, uninterrupted (CGG)n tracts suggests that they occur more frequently on genetic backgrounds which are more highly represented on fragile X chromosomes. These arrays may well be precursors from which the larger fragile X associated arrays have arisen by further expansion.
Hum Mol Genet 1994 Sep
PMID:Precursor arrays for triplet repeat expansion at the fragile X locus. 783 10

The mutation observed in the fragile X syndrome, an X-linked inherited disorder causing mental retardation, is almost exclusively an expanded CGG repeat in the first exon of the FMR1 gene. Here we describe a daughter of a female carrier, who inherited the fragile X premutation chromosome based on haplotype analysis using flanking markers. However, the CGG repeat sequence and the intragenic polymorphic marker FMRb showed the normal maternal alleles, while two other intragenic markers, FMRa and FRAXAC2 and other, more distant markers, showed the risk haplotype. Since FMRa and FRAXAC2 are located in between the markers CGG and FMRb, this results in patches of normal and fragile X sequences in the FMR1 gene of the daughter. This observation is very likely due to gene conversion. As this daughter received a normal CGG repeat region, we expect that her risk to have affected offspring is the same as the population risk. The observed phenomenon would therefore represent a back mutation at the FMR1 locus.
Hum Mol Genet 1994 Oct
PMID:Loss of mutation at the FMR1 locus through multiple exchanges between maternal X chromosomes. 784 7

Although considered the most common heritable cause of neurodevelopmental disability, precise prevalence figures for the FMR1 mutation in the general population are lacking. Since no fragile X premutation alleles have yet been observed to originate from FMR1 alleles within the normal size range, there is also little information available about the origin of the fragile X premutation and mechanisms leading to instability of the FMR1 trinucleotide repeat region. In this study, 977 genetically unrelated individuals from families unselected for mental retardation or fragile X were analyzed with Southern blot analysis for the presence of FMR1 mutations. A subgroup of subjects with evidence of a large CGG repeat number, and any available relatives, were further studied with PCR to investigate the stability of the trinucleotide repeat segment of FMR1. One subject had a 75 repeat length which was unstable (increased in size) when passed to subsequent generations. This includes one male descendent who had a premutation/full mutation mosaic pattern. Two other alleles with > or = 46 repeats from different subjects were also found to be unstable and increased in size in subsequent generations. Considering all three unstable alleles to be indicative of an evolving or actual premutation, the estimated frequency of the fragile X premutation is one in 510 X chromosomes. However, since 11 other alleles with > or = 46 repeats were found to be stable through at least one meiotic transmission, repeat length appears to be an important but not sufficient condition leading to instability of the FMR1 gene.
Hum Mol Genet 1994 Mar
PMID:Frequency and stability of the fragile X premutation. 801 50

The vast majority of individuals with the fragile X syndrome show expanded stretches of CGG repeats in the 5' non-coding region of FMR1. This expansion coincides with abnormal methylation patterns in that area resulting in the silencing of the FMR1 gene. Evidence is accumulating that this directly causes the fragile X phenotype. Very few other mutations in FMR1, causing the fragile X phenotype have been reported thus far and all concerned isolated cases. We, however, report a family, in which 11 individuals have a deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene. Although fragile X chromosomes were not detected, all 4 affected males and 2 of the carrier females show characteristics of the fragile X phenotype. Using RT-PCR we could demonstrate that FMR1 is not expressed in the affected males, strongly suggesting that the FMR1 promoter sequences 5' to the CGG repeat are missing. The deletion patients have approximately 45 CGG repeats in their FMR1 gene, though not interspersed by AGG triplets that are usually present in both normal and expanded repeats. It is hypothesized that prior to the occurrence of the deletion, an expansion of the repeat occurred, and that the deletion removed the 5' part of the CGG repeat containing the AGG triplets. Transmission of the deletion through the family could be traced back to the deceased grandfather of the affected males, which supports the hypothesis that the FMR1 gene product is not required for spermatogenesis. Finally, the data provide additional evidence that the fragile X syndrome is a single gene disorder.
Hum Mol Genet 1994 Apr
PMID:A deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene causes the clinical phenotype of the fragile X syndrome. 806 7


1 2 3 4 5 6 7 8 9 10 Next >>