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Microarray Identification of FMRP-Associated Brain mRNAs and Altered mRNA Translational Profiles in Fragile X Syndrome
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Fragile X syndrome results from the absence of the RNA binding FMR protein. Here, mRNA was coimmunoprecipitated with the FMRP ribonucleoprotein complex and used to interrogate microarrays. We identified 432 associated mRNAs from mouse brain. Quantitative RT-PCR confirmed some to be >60-fold enriched in the immunoprecipitant. In parallel studies, mRNAs from polyribosomes of fragile X cells were used to probe microarrays. Despite equivalent cytoplasmic abundance, 251 mRNAs had an abnormal polyribosome profile in the absence of FMRP. Although this represents <2% of the total messages, 50% of the coimmunoprecipitated mRNAs with expressed human orthologs were found in this group. Nearly 70% of those transcripts found in both studies contain a G quartet structure, demonstrated as an in vitro FMRP target. We conclude that translational dysregulation of mRNAs normally associated with FMRP may be the proximal cause of fragile X syndrome, and we identify candidate genes relevant to this phenotype.
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“We can thus conclude that the co-repressor activity of CYFIP1-FMRP does not affect G-quadruplex-containing mRNAs, which represent a subset of FMRP targets (Brown et al., 2001; Maurin et al., 2014; Suhl et al., 2015).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Brown et al., 2001
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“G-quadruplex mRNA is a structure bound by FMRP harbored by some of its critical targets (MAP1B, PP2AC, FMR1, SHANKL, SEMA3F) (Brown et al., 2001; Castets et al., 2005; Schaeffer et al., 2001; Zhang et al., 2014; Menon and Mihailescu, 2007).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Brown et al., 2001
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“Moreover, the G-quadruplex/FMRP complex mediates the repression activity of FMRP in translational regulation (Schaeffer et al., 2001; Brown et al., 2001; Castets et al., 2005; Melko and Bardoni, 2010; Suhl et al., 2015).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Brown et al., 2001
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“In contrast to NR2A and NR2B, the NR1 mRNA was not associated with FMRP by the coimmunoprecipitation assay (Figure 8A), nor was there coprecipitation of GAPDH mRNAs, a commonly used negative control that is believed not to be regulated by FMRP (Brown et al., 2001).”
From Regulation of Synaptic Structure and Function by FMRP-Associated MicroRNAs miR-125b and miR-132 (2010) · cites this paper as Brown et al., 2001
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“We followed the standard procedure for FMRP immunoprecipitation used to identify mRNA targets (Brown et al., 2001).”
From Regulation of Synaptic Structure and Function by FMRP-Associated MicroRNAs miR-125b and miR-132 (2010) · cites this paper as Brown et al., 2001
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“In contrast to NR2A and NR2B, the NR1 mRNA was not associated with FMRP by the coimmunoprecipitation assay (Figure 8A), nor was there coprecipitation of GAPDH mRNAs, a commonly used negative control that is believed not to be regulated by FMRP (Brown et al., 2001).”
From Regulation of Synaptic Structure and Function by FMRP-Associated MicroRNAs miR-125b and miR-132 (2010) · cites this paper as Brown et al., 2001
Experimental — accuracy not yet measuredIn the citing paper
“Encoded by the FMR1 gene, Fragile X mental retardation protein (FMRP) mostly operates as an mRNA-binding protein (Fig. 5B2) that represses translation of an emerging subset of mRNAs (Brown et al., 2001; Darnell et al., 2001; Darnell et al., 2011; Santoro et al., 2012), among other functions (Contractor et al., 2015).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Brown et al., 2001
In the citing paper
“FMRP regulates stability, subcellular transport, and translation of neuronal mRNAs encoding for proteins involved the in synaptic structure and function (58,(65)(66)(67).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [65]
In the citing paper
“the discovery that FMRP is involved in regulating the glucocorticoid receptor in the hippocampus (Brown et al., 2001).”
From Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome (2012) · cites this paper as Brown et al., 2001
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“We can thus conclude that the co-repressor activity of CYFIP1-FMRP does not affect G-quadruplex-containing mRNAs, which represent a subset of FMRP targets (Brown et al., 2001; Maurin et al., 2014; Suhl et al., 2015).”
Hyperexcitability and homeostasis in fragile X Syndrome.
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Metadata
- Authors
- Brown, V., Jin, P., Ceman, S., Darnell, J. C., O'Donnell, W. T., Tenenbaum, S. A., Jin, X., Feng, Y., Wilkinson, K. D., Keene, J. D., Darnell, R. B., & Warren, S. T.
- Affiliations
- Howard Hughes Medical Institute (US)
- Rockefeller University (US)
- Duke Medical Center (US)
- Emory University (US)
- Corresponding author
- Warren, Stephen T.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2001-11
- Volume
- 107
- Issue
- 4
- Pages
- 477-487
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2098756736
- Cited by
- 1,109
- References
- 47
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 20 · 2023: 28 · 2022: 27 · 2021: 33 · 2020: 36 · 2019: 41 · 2018: 39 · 2017: 39 · 2016: 43 · 2015: 39 · 2014: 56 · 2013: 57 · 2012: 51
- FWCI
- 33.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (T32GM008490, T32GM008169)
- National Institute of Neurological Disorders and Stroke (R01 NS34389, R01NS034389)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37 HD20521, R01 HD40647, P01 HD35576, R37HD020521, R01HD040647, P01HD035576)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- fragile X syndrome, FMRP, G-quartet, RNA-binding proteins, mouse brain, candidate genes
- MeSH terms
- Amino Acid Sequence, Animals, Brain Chemistry, Centrifugation, Density Gradient, Disease Models, Animal, Fragile X Syndrome, Humans, Ligands, Mice, Inbred C57BL, Models, Genetic, Molecular Sequence Data, Nerve Tissue Proteins, Precipitin Tests, Protein Binding, Regulatory Sequences, Nucleic Acid, Ribosomes, RNA, Messenger, Protein Biosynthesis, Polymerase Chain Reaction, Sequence Alignment, RNA-Binding Proteins, Sequence Homology, Amino Acid, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Macromolecular Substances, Mice, Fragile X Messenger Ribonucleoprotein 1, Fragile X Mental Retardation Protein
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