Understanding the molecular basis of fragile X syndrome
Human Molecular GeneticsPublished 1 April 2000Open access
P. Jin
Citations369
SJR quartileQ1
SJR score1.56
SNIP0.92
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TL;DR
The recent progress made towards understanding the molecular mechanism of CGG triplet repeats expansion and physiological function(s) of FMRP is discussed.
Abstract
Fragile X syndrome, a common form of inherited mental retardation, is mainly caused by massive expansion of CGG triplet repeats located in the 5'-untranslated region of the fragile X mental retardation-1 ( FMR1 ) gene. In patients with fragile X syndrome, the expanded CGG triplet repeats are hypermethylated and the expression of the FMR1 gene is repressed, which leads to the absence of FMR1 protein (FMRP) and subsequent mental retardation. FMRP is an RNA-binding protein that shuttles between the nucleus and cytoplasm. This protein has been implicated in protein translation as it is found associated with polyribosomes and the rough endoplasmic reticulum. We discuss here the recent progress made towards understanding the molecular mechanism of CGG repeat expansion and physiological function(s) of FMRP. These studies will not only help to illuminate the molecular basis of the general class of human diseases with trinucleotide repeat expansion but also provide an avenue to understand aspects of human cognition and intelligence.
Keywords
Biochemistry, Genetics and Molecular Biology
CellIdentification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome
3,507 Citations1991Annemieke J.M.H. Verkerk, Maura Pieretti +19 more
A fragile X site-induced breakpoint cluster region that exhibits length variation in fragile X chromosomes is identified and localization of the brain-expressed FMR-1 gene to this EcoRI fragment suggests the involvement of this gene in the phenotypic expression of the fragile X syndrome.
CellVariation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox
2,095 Citations1991Ying‐Hui Fu, Derek P.A. Kuhl +11 more
ScienceInstability of a 550-Base Pair DNA Segment and Abnormal Methylation in Fragile X Syndrome
1,492 Citations1991I. Oberlé, F. Rousseau +7 more
expression of the fragile X syndrome appears to result from a two-step mutation as well as a highly localized methylation, and can easily be detected regardless of sex or phenotypic expression.
Proceedings of the National Academy of SciencesAbnormal dendritic spines in fragile X knockout mice: Maturation and pruning deficits
1,037 Citations1997Thomas A. Comery, Jennifer B. Harris +5 more
Dendritic spines in Golgi-impregnated cerebral cortex of transgenic fragile X gene (Fmr1) knockout mice that lack expression of the protein were longer than those in wild-type mice and were often thin and tortuous, paralleling the human syndrome and suggesting that FMRP expression is required for normal spine morphological development.
CellFmr1 knockout mice: A model to study fragile X mental retardation
1,034 Citations1994Cathy E. Bakker
A knockout mouse is used as a model to elucidate the mechanisms involved in macroorchidism, abnormal behavior, and mental retardation and may serve as a valuable tool in studying the role of FMR1 in the fragile X syndrome.
ScienceA Requirement for Local Protein Synthesis in Neurotrophin-Induced Hippocampal Synaptic Plasticity
983 Citations1996Hyejin Kang, Erin M. Schuman
Two neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are able to produce a long-lasting enhancement of synaptic transmission in the hippocampus, allowing synapses to exert local control over the complement of proteins expressed at individual synaptic sites.
ScienceMapping of DNA Instability at the Fragile X to a Trinucleotide Repeat Sequence P(CCG) <i>n</i>
923 Citations1991Eric J. Kremer, Melanie Pritchard +8 more
ScienceFragile X Genotype Characterized by an Unstable Region of DNA
799 Citations1991Shuancang Yu, Melanie Pritchard +10 more
This probe provides a means with which to analyze fragile X pedigrees and is a diagnostic reagent for the fragile X genotype.
The American Journal of Human GeneticsElevated Levels of FMR1 mRNA in Carrier Males: A New Mechanism of Involvement in the Fragile-X Syndrome
771 Citations2000Flora Tassone, Randi J. Hagerman +4 more
Current results support a mechanism of involvement in premutation carriers, in which reduced translational efficiency is at least partially compensated through increased transcriptional activity in the full-mutation range as the FMR1 gene is silenced.
Science<i>FMR1</i> Protein: Conserved RNP Family Domains and Selective RNA Binding
738 Citations1993Claude T. Ashley, Keith D. Wilkinson +2 more
Proceedings of the National Academy of SciencesFragile X mental retardation protein is translated near synapses in response to neurotransmitter activation
644 Citations1997Ivan Jeanne Weiler, Scott A. Irwin +8 more
It is suggested that rapid production of FMRP near synapses in response to activation may be important for normal maturation of synaptic connections.
CellThe protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein
642 Citations1993Haruhiko Siomi, Mikiko C. Siomi +2 more
Nature GeneticsA point mutation in the FMR-1 gene associated with fragile X mental retardation
621 Citations1993Kristel De Boulle, Annemieke J.M.H. Verkerk +8 more
The results suggest that mutations in FMR–1 are directly responsible for fragile X syndrome, irrespective of possible secondary effects caused by FRAXA.
CellTrinucleotide repeats that expand in human disease form hairpin structures in vitro
568 Citations1995A. Marquis Gacy, Geoffrey M. Goellner +3 more
Hairpin formation provides a potential structural basis for the constancy of the CCG region of the Huntington's disease gene in individuals and explains the stabilizing effects of AGG interruptions in FMR1 alleles.
Journal of NeuroscienceFragile X Mental Retardation Protein: Nucleocytoplasmic Shuttling and Association with Somatodendritic Ribosomes
535 Citations1997Yue Feng, Claire‐Anne Gutekunst +4 more
Dendritic localization, which was confirmed by co-fractionation of F MRP with synaptosomal ribosomes, suggests a possible role of FMRP in the translation of proteins involved in dendritic structure or function and relevant for the mental retardation occurring in fragile X syndrome.
Molecular CellFMRP Associates with Polyribosomes as an mRNP, and the I304N Mutation of Severe Fragile X Syndrome Abolishes This Association
515 Citations1997Yue Feng, Devin Absher +4 more
It is shown here that normal FMRP associates with elongating polyribosomes via large mRNP particles, implying that the mechanism of the severe phenotype in the I304N patient lies in the sequestration of bound mRNAs in nontranslatable mR NP particles.
Human GeneticsFurther segregation analysis of the fragile X syndrome with special reference to transmitting males
510 Citations1985Stephanie L. Sherman, P. A. Jacobs +8 more
It is suggested that obligate carrier mothers and daughters of intellectually normal transmitting males are rarely, if ever, mentally impaired and that the sibs of transmitting Males are much less likely to be retarded than the sIBs of mentally impaired males.
American Journal of Medical GeneticsAnalysis of neocortex in three males with the fragile X syndrome
509 Citations1991Veronica J. Hinton, W. Ted Brown +2 more
Nature GeneticsEvidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I
483 Citations1993Ming‐Yi Chung, Laura P.W. Ranum +4 more
Nature GeneticsLength of uninterrupted CGG repeats determines instability in the FMR1 gene
482 Citations1994Evan E. Eichler, Jeanette J. A. Holden +7 more
Analysis of 84 human X chromosomes for the presence of interrupting AGG trinucleotides within the CGG repeat tract of the FMR1 gene revealed that most alleles possess two interspersed AGGs and that the longest tract of uninterrupted CGG repeats is usually found at the 3′ end.
CellEssential role for KH domains in RNA binding: Impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile X syndrome
446 Citations1994Haruhiko Siomi, Mleyoung Choi +3 more
An essential role for KH domains in RNA binding is demonstrated and a previously reported mutation in a highly conserved residue of one of its two KH domains results in mental retardation, which strengthens the connection between fragile X syndrome and loss of the RNA binding activity of FMR1.
CellA Novel Mutation Avoidance Mechanism Dependent on S. cerevisiae RAD27 Is Distinct from DNA Mismatch Repair
440 Citations1997Daniel X. Tishkoff, Nicole Filosi +2 more
The observations suggest that the majority of replication errors that accumulate in rad27 strains are processing by double-strand break repair, while a smaller percentage are processed by a mutagenic repair pathway.
Nature GeneticsTissue specific expression of FMR–1 provides evidence for a functional role in fragile X syndrome
395 Citations1993Heather L. Hinds, Claude T. Ashley +5 more
The early embryonic onset and tissue specificity of FMR–1 gene expression is consistent with involvement in the fragile X phenotype, and also suggests additional organ systems in which clinical manifestations of reduced FMR-1 gene Expression may occur.
Annals of Human GeneticsThe marker (X) syndrome: a cytogenetic and genetic analysis
389 Citations1984Stephanie L. Sherman, N.E. Morton +2 more
The cytogenetic and segregation analysis of 110 pedigrees of the mar (X) syndrome indicated an inverse relationship between IQ and the mar(X) frequency in females but not in males, but in females it was restricted to those of normal intelligence, retarded females showing no significant effect.
Human Molecular GeneticsThe fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals
384 Citations1996Derek E. Eberhart
Immunolocalization analysis of FMRP truncation and fusion constructs revealed a nuclear localization signal in the amino terminus of F MRP as well as a nuclear export signal (NES) encoded by exon 14, which suggests that fragile X syndrome may result from altered translation of transcripts which normally bind to FMRp.
CellCryptic and polar variation of the fragile X repeat could result in predisposing normal alleles
360 Citations1994Catherine B. Kunst
Normal alleles with greater than 24 perfect 3' CGG repeats appear more frequently on haplotypes overrepresented among fragile X chromosomes, suggesting stability differences between the leading and lagging strands of DNA replication.
ScienceTranslational Suppression by Trinucleotide Repeat Expansion at <i>FMR1</i>
355 Citations1995Yue Feng, Fuping Zhang +5 more
Results suggest that a structural RNA transition beyond 200 repeats impedes the linear 40S migration along the 5'-untranslated region of the FMR1 gene and results in translational inhibition by trinucleotide repeat expansion.
The EMBO JournalThe fragile X mental retardation syndrome protein interacts with novel homologs FXR1 and FXR2.
330 Citations1995Yingying Zhang, J. P. O’Connor +5 more
Cloned and sequenced a protein that interacts tightly with FMR1 in vivo and in vitro, and it is likely that FXR1 and FXR2 are likely to play important roles in the function of F MR1 and in the pathogenesis of the Fragile X Mental Retardation Syndrome.
Journal of Biological ChemistryEnzymes and Reactions at the Eukaryotic DNA Replication Fork
328 Citations1997Robert A. Bambara, Richard S. Murante +1 more
This work will focus on recent findings concerning specific enzymatic reactions necessary for the growth of the eukaryotic replication fork.
Nature GeneticsAcetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells
324 Citations1999Bradford Coffee, Fuping Zhang +2 more
It is demonstrated that the 5´ end of FMR1 is associated with acetylated histones H3 and H4 in cells from normal individuals, but acetylation is reduced in Cells from fragile X patients, the first description of loss of histone acetylations at a specific locus in human disease.
Nature GeneticsThe full mutation in the FMR–1 gene of male fragile X patients is absent in their sperm
304 Citations1993Edwin Reyniers, Lieve Vits +9 more
Study of FMR–1 in sperm of four male fragile X patients showed that only the premutation was present in their sperm, although they had a full mutation in peripheral lymphocytes, which might suggest that expansion of the premutations to the full mutations in FMR-1 does not occur in meiosis but in a postzygotic stage.
NeuroscienceFragile X mouse: strain effects of knockout phenotype and evidence suggesting deficient amygdala function
297 Citations1999William Paradee, Haley E. Melikian +4 more
Examination of late-phase hippocampal long-term potentiation in the Fmrl knockout mice suggests that amygdala disturbances may also be involved in fragile X syndrome and examines spatial learning in the knockout mice using the hippocampus-dependent Morris water maze.
CellThree-Dimensional Structure and Stability of the KH Domain: Molecular Insights into the Fragile X Syndrome
283 Citations1996Giovanna Musco, Günter Stier +5 more
This work presents the three-dimensional solution structure of the KH module, a sequence motif found in a number of proteins that are known to be in close association with RNA, and suggests a potential surface for RNA binding centered on the loop between the first two helices.
Nature GeneticsHuman and murine FMR-1: alternative splicing and translational initiation downstream of the CGG–repeat
263 Citations1993Claude T. Ashley, James S. Sutcliffe +5 more
The isolation and characterization of cDNA clones encoding the murine homologue, fmr–1, are reported, which exhibit marked sequence identity with the human gene, including the conservation of the CGG repeat.
Journal of Medical GeneticsThe fragile X syndrome.
263 Citations1998Bert Ba de Vries, D. J. J. Halley +2 more
The cloning of the FMR1 gene led to the characterisation of its protein product FMRP, encouraged further clinical studies, and opened up the possibility of more accurate family studies and fragile X screening programmes.
Proceedings of the National Academy of SciencesOn the nature and differential distribution of mRNAs in hippocampal neurites: implications for neuronal functioning.
261 Citations1994Kevin Miyashiro, Marc A. Dichter +1 more
Direct evidence is presented that an unexpectedly large number of mRNAs, including members of the glutamate receptor family, second messenger system, and components of the translational control apparatus, are present in individual processes of hippocampal cells in culture.
The EMBO JournalFXR1, an autosomal homolog of the fragile X mental retardation gene.
240 Citations1995M. C. Siomi, Haruhiko Siomi +4 more
It is demonstrated that FMR1 and FXR1 are members of a gene family and suggest a biological role forFXR1 that is related to that of F MR1, and 3′ untranslated regions (3′UTRs) of the human and Xenopus laevis FXR 1 mRNAs are strikingly conserved, suggesting conservation of an important function.
Human Molecular GeneticsThe fragile X mental retardation protein is associated with poly(A)+ mRNA in actively translating polyribosomes
233 Citations1997François Corbin
Evidence is presented that virtually all detectable cytoplasmic FMRP in mouse NIH 3T3 and human HeLa cells is found strictly in association with mRNA in actively translating polyribosomes, suggesting that FMR1 expression is not cell cycle regulated and that F MRP might have a house-keeping function.
PubMedAnalysis of a CGG sequence at the FMR-1 locus in fragile X families and in the general population.
227 Citations1993K. Snow, L. Doud +4 more
Describing a CGG repeat at the FMR-1 locus in more than 100 families presenting for fragile X testing and in 247 individuals from the general population suggests that the frequency of unstable alleles in the generalpopulation may be approximately 1%.
Proceedings of the National Academy of SciencesHairpins are formed by the single DNA strands of the fragile X triplet repeats: structure and biological implications.
227 Citations1995Xuemin Chen, S. V. Santhana Mariappan +7 more
Hairpin formation could account for the specific methylation of the CpG island in the fragile X repeat that occurs during inactivation of the FMR1 gene during the onset of the disease.
Molecular and Cellular BiologyStability of a CTG/CAG Trinucleotide Repeat in Yeast Is Dependent on Its Orientation in the Genome
218 Citations1997Catherine H. Freudenreich, Jeffrey B. Stavenhagen +1 more
The orientation dependence of CTG/CAG tract instability seen in this yeast system supports models involving hairpin-mediated polymerase slippage previously proposed for trinucleotide repeat expansion.
Human Molecular GeneticsSynergistic Effect of Histone Hyperacetylation and DNA Demethylation in the Reactivation of the FMR1 Gene
216 Citations1999Pietro Chiurazzi, Maria Grazia Pomponi +4 more
A marked synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of FMR1 full mutations is shown, showing a 2- to 5-fold increase in FMR 1 mRNA levels obtained with 5-azadC alone.
Human Molecular GeneticsIn Vitro Reactivation of the FMR1 Gene Involved in Fragile X Syndrome
202 Citations1998Pietro Chiurazzi, Maria Grazia Pomponi +3 more
It is reported 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, which correlates with the extent of promoter demethylation, determined by restriction analysis with methylation-sensitive enzymes.
Nature GeneticsCharacterization of the full fragile X syndrome mutation in fetal gametes
196 Citations1997Henry Malter, Jane Iber +6 more
Analysis of intact ovaries of full mutation fetuses shows that only full expansion alleles can be detected in oocytes (but in the unmethylated state), discounting the hypothesis that the germline is protected from full expansion and suggest full mutation contraction in the immature testis.
ScienceRequirement of the Yeast <i>RTH1</i> 5′ to 3′ Exonuclease for the Stability of Simple Repetitive DNA
196 Citations1995Robert E. Johnson, Gopala Kovvali +2 more
Epistasis analyses were consistent with the hypothesis that this RTH1-encoded nuclease has a role in the MSH2-MLH-1-PMS1 mismatch repair pathway, which is shown to increase the rate of instability of simple repetitive DNA by as much as 280 times.
Journal of Biological ChemistryPurified Recombinant Fmrp Exhibits Selective RNA Binding as an Intrinsic Property of the Fragile X Mental Retardation Protein
192 Citations1998Victoria Brown, Kersten M. Small +5 more
Baculovirus-expressed and affinity-purified FLAG-tagged murine Fmrp was shown to bind directly to both ribonucleotide homopolymers and human brain mRNA, andFLAG-Fmrp is shown as a suitable reagent for structural characterization and identification of cognate RNA ligands.
Human Molecular GeneticsFine structure of the human FMR1 gene
186 Citations1993Evan E. Eichler, Stephen Richards +2 more
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.
Molecular and Cellular BiologyIsolation of an FMRP-Associated Messenger Ribonucleoprotein Particle and Identification of Nucleolin and the Fragile X-Related Proteins as Components of the Complex
181 Citations1999Stephanie Ceman, Victoria Brown +1 more
The identification of nucleolin, a known component of other mRNPs, adds a new dimension to the analysis of F MRP function, and the approach described should also allow the identification of the remaining unknown proteins of this FMRP-associated mRNP as well as the other bound mRNAs.
Molecular and Cellular BiologyDestabilization of Yeast Micro- and Minisatellite DNA Sequences by Mutations Affecting a Nuclease Involved in Okazaki Fragment Processing ( <i>rad27</i> ) and DNA Polymerase δ ( <i>pol3-t</i> )
179 Citations1998Robert J. Kokoska, Lela Stefanovic +4 more
It is found that rad27 and pol3-01 (an allele carrying a mutation in the “proofreading” exonuclease domain of DNA polymerase δ) mutations were synthetically lethal and destabilized both classes of repeats, although the types of tract alterations observed in the two mutant strains were different.
Molecular CellInhibition of FEN-1 Processing by DNA Secondary Structure at Trinucleotide Repeats
177 Citations1999Craig Spiro, Richard Pelletier +8 more
It is shown that secondary structure can, indeed, play a role in expansion by a FEN-1-dependent mechanism, and alternative pathways to simple inhibition of flap processing contribute to expansion when Fen-1 is absent from the cell.
JAMAAdvances in Molecular Analysis of Fragile X Syndrome
176 Citations1994Stephen T. Warren
Advances have led to highly accurate laboratory diagnoses of both carrier and affected individuals as well as markedly improved prenatal diagnosis, and a previously unrecognized class of mutation, later found responsible for several other important genetic diseases, has emerged.
Nature GeneticsMitotic stability of fragile X mutations in differentiated cells indicates early post–conceptional trinucleotide repeat expansion
174 Citations1993Doris Wöhrle, Ingeborg Hennig +2 more
It is demonstrated that somatic variation of CGG repeat length is based on a mosaic of cells with different but stable FMR–1 alleles and does not reflect permanent mitotic instability.
Journal of NeuroscienceProtein-synthetic machinery at postsynaptic sites during synaptogenesis: a quantitative study of the association between polyribosomes and developing synapses
174 Citations1986Oswald Steward, PM Falk
Spin-associated polyribosomes represent a structural specialization of dendrites at sites of synapse construction and as such may represent a marker for growing synapses, and it is proposed that these elements produce protein(s) that are critically involved in the formation of the synaptic contact.
PubMedA microdeletion of less than 250 kb, including the proximal part of the FMR-I gene and the fragile-X site, in a male with the clinical phenotype of fragile-X syndrome.
173 Citations1992Doris Wöhrle, Dieter Kotzot +8 more
Evidence is presented that a deletion including the HTF island and exons of the FMR-1 gene was detected in a fragile X-negative mentally retarded male who presented the clinical phenotype of the fragile-X syndrome.
Human Molecular GeneticsSequence analysis of the fragile X trinucleotide repeat: implications for the origin of the fragile X mutation
156 Citations1994Karen Snow, David J. Tester +3 more
Results suggest that evolution of fragile X full mutations could involve 4 definable stages: 1) ancestral events leading to the formation of predisposing alleles which have large total repeat length (e.g. between 35 to 50) but no AGG or 1 AGG; 2) gradual slippage of these predisposingalleles to small premutations (S alleles); 3) conversion from S alleles to larger premutations; 4) massive expansion from a Z allele to a full mutation
American Journal of Medical GeneticsAnalysis of full fragile X mutations in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development
156 Citations1992Didier Devys, Valérie Biancalana +4 more
The results validate the analysis of chorionic villi for direct prenatal diagnosis of the fragile X syndrome and indicate that somatic heterogeneity of the full mutation is established during the very early stages of embryogenesis.
Journal of NeuroscienceProtein-synthetic machinery beneath postsynaptic sites on CNS neurons: association between polyribosomes and other organelles at the synaptic site
144 Citations1988Oswald Steward, T.M. Reeves
It was found that in both the dentate gyrus and hippocampus, about 50% of the polyribosomes that were present beneath the base of spines were associated with membranous cisterns, which is similar in spines with spine apparatuses and spines without a spine apparatus.
Human Molecular GeneticsFMRP is associated to the ribosomes via RNA
140 Citations1996Filippo Tamanini
It was shown that FMRP can associate to ribosomes and that this binding most likely occurs via RNA, and the observation that the binding of F MRP, containing an lle304Asn substitution, to the high molecular weight complex is reduced indicates that the interaction to the complex indeed occurs via FMRp and not via other RNA binding proteins.
Human Molecular GeneticsA heterogeneous set of FMR1 proteins is widely distributed in mouse tissues and is modulated in cell culture
137 Citations1995Edward W. Khandjian, F. Anny +6 more
It is reported that expression of the FMR1 gene is modulated in proliferating and quiescent primary mouse kidney cell cultures with an inverse relationship between levels of F MR1 mRNA and of its encoded proteins, suggesting that FMRPs are highly stable in quiescence cells and that F MRP expression is likely post-transcriptionally controlled.
American Journal of Medical GeneticsMolecular cytogenetic study of supernumerary marker chromosomes in an unselected group children
136 Citations1995Claus Højbjerg Gravholt, Ursula Friedrich
An unselected group of 24 children with small supernumerary marker chromosomes, found in a large sample of 34,910 consecutive newborns karyotyped at birth, are reported on, with the use of in situ hybridization with alpha-satellite centromere probes and satellite III, ribosomal and beta-s satellite DNA probes.
Human Molecular GeneticsA Novel RNA-binding Nuclear Protein That Interacts With the Fragile X Mental Retardation (FMR1) Protein
134 Citations1999Barbara Bardoni, Annette Schenck +1 more
NUFIP mRNA expression is strikingly similar to that of the FMR1 gene in neurones of cortex, hippocampus and cerebellum and indicates a specific nuclear role for FMRP, which can shuttle between the nucleus and the cytoplasm.
PubMedFragile X gene instability: anchoring AGGs and linked microsatellites.
129 Citations1995Ning Zhong, Wei Yang +2 more
Analysis of a set of nonhuman primate samples showed that long pure CGG tracks are variable in size and are located within the 3' region, which suggests that polar instability within FMR1 is evolutionarily quite old.
Human Molecular GeneticsCis-acting modifiers of expanded CAG/CTG triplet repeat expandability: associations with flanking GC content and proximity to CpG islands
122 Citations1999Graham Brock
Data are presented that provide the first insights into the molecular bases of cis -acting flanking sequences modifying the relative mutability of dispersed expanded human triplet repeats and demonstrate that the most expandable loci are all located within CpG islands.
Human Molecular GeneticsDifferent Targets for the Fragile X-Related Proteins Revealed by Their Distinct Nuclear Localizations
113 Citations1999Filippo Tamanini, Carola Bontekoe +8 more
Molecular dissection of the shuttling routes used by the FXR proteins suggests that they transport different RNAs, indicating that the association with polyribosomes regulates theshuttling process.
Human Molecular GeneticsHaplotype and interspersion analysis of the FMR1 CGG repeat identifies two different mutational pathways for the origin of the fragile X syndrome
102 Citations1996Evan E. Eichler
The present data support a model in which there are at least two different mutational pathways predisposing alleles to instability and hyperexpansion associated with the fragile X syndrome.
RNADissecting FMR1, the protein responsible for fragile X syndrome, in its structural and functional domains
96 Citations1999Salvatore Adinolfi, Claudia Bagni +4 more
It is concluded that FMR1 is a protein with multiple sites of interaction with RNA: sequence specificity is most likely achieved by the whole block that comprises the first approximately 400 residues, whereas the C-terminus provides a nonspecific binding surface.
Molecular and Cellular BiologyStability of the Human Fragile X (CGG) <sub>n</sub> Triplet Repeat Array in <i>Saccharomyces cerevisiae</i> Deficient in Aspects of DNA Metabolism
95 Citations1999Peter J. White, Rhona H. Borts +1 more
array contraction occurred in an orientation-dependent manner in most mutant backgrounds, but loss of the Sgs1p resulted in a generalized increase in array stability in both orientations, and FMR1 arrays had a 10-fold-elevated frequency of expansion in a rad27 background, providing evidence for a role in lagging-strand Okazaki fragment processing in (CGG) n triplet repeat expansion.
Nucleic Acids ResearchNucleotide excision repair affects the stability of long transcribed (CTG*CAG) tracts in an orientation-dependent manner in Escherichia coli
86 Citations1999Paweł Parniewski, Albino Bacolla +2 more
It is proposed that transcription transiently dissociates the triplet repeat complementary strands enabling the non-transcribed strand to fold into a hairpin conformation which is then sufficiently stable that replication bypasses the hairpin to give large deletions.
Human Molecular GeneticsCharacterization of FMR1 proteins isolated from different tissues
84 Citations1995C. Verhelj, Esther de Graaff +8 more
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.
Biochemistry and Cell BiologyBiology of the fragile X mental retardation protein, an RNA-binding protein
70 Citations1999Édouard W. Khandjian
The complex expression patterns of the FMR1 gene family in different cells and tissues suggest that independent, however similar, functions for each of the three FMR-related proteins might be expected in the selection and metabolism of tissue-specific classes of mRNA.
Human GeneticsGenotype mosaicism in fragile X fetal tissues
63 Citations1992Doris W�hrle, MarkC. Hirst +3 more
The results suggest that the heterogeneity occurs in all fetal tissues, but that the pattern of fragments observed varies between tissues, and that methylation across the region also varies.
GenomicsLong Uninterrupted CGG Repeats within the First Exon of the Human FMR1 Gene Are Not Intrinsically Unstable in Transgenic Mice
60 Citations1998Christian Lavedan, Ed Grabczyk +2 more
In an attempt to create a mouse model for the CGG repeat instability seen in Fragile X syndrome, transgenes corresponding to FMR1 premutation alleles are constructed and remain stable in transgenic mice.
PubMedFMR1 premutation allele (CGG)81 is stable in mice.
56 Citations1998Bontekoe Cj, de Graaff E +3 more
In all meiosis and mitosis tested, the repeat inherited stably, suggesting that other factors might be important in repeat (in)stability.
Human Molecular GeneticsFully Expanded FMR1CGG Repeats Exhibit a Length-and Differentiation-Dependent Instability in Cell Hybrids That is Independent of DNA Methylation
36 Citations1999Robert Burman, Bradley W. Popovich +2 more
The results indicate that the determinants of CGG repeat stability are more complex than generally believed, and suggest an unexpected role for cellular differentiation in this process.
Journal of Biological ChemistryAbasic Sites Induce Triplet-repeat Expansion during DNA Replication in Vitro
30 Citations1999Tara Lyons‐Darden, Michael D. Topal
It is shown that a single abasic site analog, synthesized in the triplet-repeat tract at the 5′ end of the template strand, induced dramatic TRE during DNA synthesis, implying that DNA damage can play a significant role in generating TRE in vivo.
Journal of Inherited Metabolic DiseaseThe fragile X syndrome
21 Citations1997A. T. Hoogeveen, B. A. Oostra
It is postulate that FMRP is involved in the transport of RNA and/or proteins from the nucleus to the cytoplasm and the target signals necessary for this intracellular transport are present in F MRP.
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