Characterization and localization of the FMR-1 gene product associated with fragile X syndrome

Verheij, Coleta; Bakker, Cathy; Graaff, Esther de; Keulemans, J. L. M.; Willemsen, Rob; Verkerk, Annemieke J.M.H.; Galjaard, H.; Reuser, A. J. J.; Hoogeveen, André T.; Oostra, Ben A.

doi:10.1038/363722a0

Cited by 303 publications

(239 citation statements)

References 17 publications

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“…FMRP contains amino acid domains that are common among RNA-binding proteins and has been demonstrated to interact with RNA homopolymers as well as with a subset of brain mRNAs, including its own message Siomi et al, 1993). Initial immunocytochemical studies suggested that FMRP localizes predominantly to cytoplasm (Devys et al, 1993;Verheij et al, 1993). Molecular studies, however, have demonstrated the presence of both nuclear localization and nuclear export signals within FMRP, suggesting the potential to shuttle between the nuclear and cytoplasmic compartments (Eberhart et al, 1996).…”

Section: Abstract: Fragile X Syndrome; Mental Retardation; Ribosomesmentioning

confidence: 99%

Fragile X Mental Retardation Protein: Nucleocytoplasmic Shuttling and Association with Somatodendritic Ribosomes

et al. 1997

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Fragile X syndrome, a leading cause of inherited mental retardation, is attributable to the unstable expansion of a CGGrepeat within the FMR1 gene that results in the absence of the encoded protein. The fragile X mental retardation protein (FMRP) is a ribosome-associated RNA-binding protein of uncertain function that contains nuclear localization and export signals. We show here detailed cellular localization studies using both biochemical and immunocytochemical approaches. FMRP was highly expressed in neurons but not glia throughout the rat brain, as detected by light microscopy. Although certain structures, such as hippocampus, revealed a strong signal, the regional variation in staining intensity appeared to be related to neuron size and density. In human cell lines and mouse brain, FMRP co-fractionated primarily with polysomes and rough endoplasmic reticulum. Ultrastructural studies in rat brain revealed high levels of FMRP immunoreactivity in neuronal perikarya, where it is concentrated in regions rich in ribosomes, particularly near or between rough endoplasmic reticulum cisternae. Immunogold studies also provided evidence of nucleocytoplasmic shuttling of FMRP, which was localized in neuronal nucleoplasm and within nuclear pores. Moreover, labeling was observed in large-and small-caliber dendrites, in dendritic branch points, at the origins of spine necks, and in spine heads, all known locations of neuronal polysomes. Dendritic localization, which was confirmed by co-fractionation of FMRP 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.

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Section: Abstract: Fragile X Syndrome; Mental Retardation; Ribosomesmentioning

confidence: 99%

Fragile X Mental Retardation Protein: Nucleocytoplasmic Shuttling and Association with Somatodendritic Ribosomes

et al. 1997

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“…It has also been observed that the NLS is frequently located adjacent to or overlapping with the nucleic acid binding site [5]. A characteristic RNA-binding motif is the KH domain [6-81, which is generally present in one to a few copies in most of the known members of this protein family, which have been detected either in the nucleus [9 11] or in the cytoplasm [12][13][14][15]. Vigilin is a unique member of this group in that it contains 14 KH domains in series, which account for the major part of the 150 kDA protein.…”

Section: Introductionmentioning

confidence: 99%

Vigilin contains a functional nuclear localisation sequence and is present in both the cytoplasm and the nucleus

et al. 1996

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Vigilin is a member of the KH protein family and contains 14 tandemly arranged potential RNA-binding domains. Between KH domains 2 and 3 we have identified a nuclear localization sequence by cloning this sequence into the NH2-terminal region of phage T7 RNA polymerase as a reporter protein and by showing its transfer into the nucleus. Furthermore we provide experimental evidence that Vigilin is present both in the nucleus and in the cytoplasm in similar concentrations. These observations support the notion that Vigilin may shuttle between nucleus and cytoplasm presumably in contact with RNA molecules.

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“…An expansion of the CGG repeat is associated with abnormal DNA methylation of both a nearby CpG island and the repeat itself. As a result, the FMR1 locus becomes silent at the transcriptional level and thus no translation occurs (Siomi et al 1993;Verheij et al 1993). It is therefore clear that the pathophysiological mechanisms leading to the symptoms in fragile X syndrome can be elucidated by studying the function of the FMR1 gene.…”

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confidence: 99%

A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins

Ishizuka¹,

Siomi²,

Siomi³

2002

Genes Dev.

549

427

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Fragile X syndrome is a common form of inherited mental retardation caused by the loss of FMR1 expression. The FMR1 gene encodes an RNA-binding protein that associates with translating ribosomes and acts as a negative translational regulator. In Drosophila, the fly homolog of the FMR1 protein (dFMR1) binds to and represses the translation of an mRNA encoding of the microtuble-associated protein Futsch. We have isolated a dFMR1-associated complex that includes two ribosomal proteins, L5 and L11, along with 5S RNA. The dFMR1 complex also contains Argonaute2 (AGO2) and a Drosophila homolog of p68 RNA helicase (Dmp68). AGO2 is an essential component for the RNA-induced silencing complex (RISC), a sequence-specific nuclease complex that mediates RNA interference (RNAi) in Drosophila. We show that Dmp68 is also required for efficient RNAi. We further show that dFMR1 is associated with Dicer, another essential component of the RNAi pathway, and microRNAs (miRNAs) in vivo, suggesting that dFMR1 is part of the RNAi-related apparatus. Our findings suggest a model in which the RNAi and dFMR1-mediated translational control pathways intersect in Drosophila. Our findings also raise the possibility that defects in an RNAi-related machinery may cause human disease.

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Characterization and localization of the FMR-1 gene product associated with fragile X syndrome

Cited by 303 publications

References 17 publications

Fragile X Mental Retardation Protein: Nucleocytoplasmic Shuttling and Association with Somatodendritic Ribosomes

Fragile X Mental Retardation Protein: Nucleocytoplasmic Shuttling and Association with Somatodendritic Ribosomes

Vigilin contains a functional nuclear localisation sequence and is present in both the cytoplasm and the nucleus

A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins

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