Analysis of FMRP mRNA target datasets reveals highly associated mRNAs mediated by G-quadruplex structures formed via clustered WGGA sequences
Open accessAbstract
Fragile X syndrome, a common cause of intellectual disability and a well-known cause of autism spectrum disorder, is the result of loss or dysfunction of fragile X mental retardation protein (FMRP), a highly selective RNA-binding protein and translation regulator. A major research priority has been the identification of the mRNA targets of FMRP, particularly as recent studies suggest an excess of FMRP targets among genes implicated in idiopathic autism and schizophrenia. Several large-scale studies have attempted to identify mRNAs bound by FMRP through several methods, each generating a list of putative target genes, leading to distinct hypotheses by which FMRP recognizes its targets; namely, by RNA structure or sequence. However, no in depth analyses have been performed to identify the level of consensus among the studies. Here, we analyze four large FMRP target datasets to generate high-confidence consensus lists, and examine all datasets for sequence elements within the target RNAs to validate reported FMRP binding motifs (GACR, ACUK and WGGA). We found GACR to be highly enriched in FMRP datasets, while ACUK was not. The WGGA pattern was modestly enriched in several, but not all datasets. The previous association between FMRP and G-quadruplexes prompted the analysis of the distribution of WGGA in the target genes. Consistent with the requirements for G-quadruplex formation, we observed highly clustered WGGA motifs in FMRP targets compared with other genes, implicating both RNA structure and sequence in the recognition motif of FMRP. In addition, we generate a list of the top 40 FMRP targets associated with FXS-related phenotypes.
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The co-repressor activity of CYFIP1-FMRP does not affect G-quadruplex-containing mRNAs, which represent a subset of FMRP targets.
“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 Suhl et al., 2015
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Self-citationSporadic autism exomes reveal a highly interconnected protein network of de novo mutations
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FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism
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Hagerman, R. J., Berry-Kravis, E., Hazlett, H. C., Bailey, D. B., Moine, H., Kooy, R. F., Tassone, F., Gantois, I., Sonenberg, N., Mandel, J. L., et al. (2017) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2017.65 · Cited by 838 · see citing works
Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back
Gross, C., Hoffmann, A., Bassell, G. J., & Berry-Kravis, E. M. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0355-9 · Cited by 105 · see citing works
Self-citationDeletion of Fmr1 alters function and synaptic inputs in the auditory brainstem
Rotschafer, S. E., Marshak, S., & Cramer, K. S. (2015) · PLOS ONE · doi:10.1371/journal.pone.0117266 · Cited by 72 · see citing works
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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).”
- Authors
- Suhl, J. A., Chopra, P., Anderson, B. R., Bassell, G. J., & Warren, S. T.
- Affiliations
- Emory University (US)
- Corresponding author
- Warren, Stephen T.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-05-29
- Volume
- 23
- Issue
- 20
- Pages
- 5479-5491
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC4168832
- OpenAlex
- W2118122718
- Cited by
- 81
- References
- 7
- Citations by year
- 2026: 2 · 2025: 3 · 2023: 3 · 2022: 6 · 2021: 9 · 2020: 13 · 2019: 6 · 2018: 10 · 2017: 8 · 2016: 6 · 2015: 13 · 2014: 2
- FWCI
- 6.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Emory University
- National Institutes of Health
- National Institute of Mental Health (R01MH085617, T32MH087977, R01MH102690)
- National Institute of Neurological Disorders and Stroke (F32NS083205)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 24064, P30HD024064)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- FMRP, fragile X syndrome, G-quadruplex, autism spectrum disorder, schizophrenia
- MeSH terms
- Amino Acid Sequence, Binding Sites, Fragile X Syndrome, Humans, RNA, Messenger, Amino Acid Motifs, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, G-Quadruplexes
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