Molecular Mechanisms of Fragile X Syndrome: A Twenty-Year Perspective
Abstract
Fragile X syndrome (FXS) is a common form of inherited intellectual disability and is one of the leading known causes of autism. The mutation responsible for FXS is a large expansion of the trinucleotide CGG repeat in the 5' untranslated region of the X-linked gene FMR1. This expansion leads to DNA methylation of FMR1 and to transcriptional silencing, which results in the absence of the gene product, FMRP, a selective messenger RNA (mRNA)-binding protein that regulates the translation of a subset of dendritic mRNAs. FMRP is critical for mGluR (metabotropic glutamate receptor)-dependent long-term depression, as well as for other forms of synaptic plasticity; its absence causes excessive and persistent protein synthesis in postsynaptic dendrites and dysregulated synaptic function. Studies continue to refine our understanding of FMRP's role in synaptic plasticity and to uncover new functions of this protein, which have illuminated therapeutic approaches for FXS.
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S6K1 acts downstream of TORC1 to drive EIF4E-regulated initiation of translation and dampens translation of FMRP-regulated mRNAs by phosphorylating FMRP.
“S6K1 has been shown to act downstream of TORC1 to drive EIF4E-regulated initiation of translation (Richter et al., 2015), and dampens translation of FMRP-regulated mRNAs by phosphorylating FMRP (Santoro et al., 2012).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Santoro et al., 2012
FMR1 is an RNA-binding protein that regulates neuronal protein synthesis.
“FMR1 is an RNA-binding protein that regulates neuronal protein synthesis 91 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [91]
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“Additionally, it was found that FMRP targets a subset of mRNA encoding proteins critically involved in lipid synthesis and transport [6].”
BackgroundInfluential
- Authors
- Santoro, M. R., Bray, S. M., & Warren, S. T.
- Affiliations
- Emory University (US)
- Venue
- Annual Review of Pathology: Mechanisms of Disease
- Publisher
- Annual Reviews
- Published
- 2012-02-28
- Volume
- 7
- Issue
- 1
- Pages
- 219-245
- ISSN
- 1553-4006 (ISSN-L)
- 1553-4014
- OpenAlex
- W2123824748
- Cited by
- 528
- References
- 27
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 31 · 2023: 20 · 2022: 23 · 2021: 34 · 2020: 46 · 2019: 34 · 2018: 47 · 2017: 55 · 2016: 54 · 2015: 48 · 2014: 47 · 2013: 34 · 2012: 23
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Pathology Mechanisms of Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM008490)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 024064, HD020521, R01HD020521, P30HD024064)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- fragile X syndrome, FMR1 gene, FMRP, CGG repeat expansion, DNA methylation, transcriptional silencing, intellectual disability, autism spectrum disorder, synaptic plasticity, treatment options
- MeSH terms
- Animals, Dendrites, Fragile X Syndrome, Humans, Neuronal Plasticity, Phosphorylation, RNA, Messenger, Receptors, Metabotropic Glutamate, Trinucleotide Repeats, Fragile X Messenger Ribonucleoprotein 1
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