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Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures
Open accessAbstract
Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interaction with the large-conductance calcium-activated potassium (BK) channels that modulate AP width. These results reveal a presynaptic- and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.
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“and a translation-independent function was also described for FMRP (Myrick 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 Myrick et al., 2015
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Self-citationAltered synaptic plasticity in a mouse model of fragile X mental retardation
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A point mutation in the FMR-1 gene associated with fragile X mental retardation
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Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder
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Molecular Mechanisms of Fragile X Syndrome: A Twenty-Year Perspective
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Self-citationMuddashetty, R. S., Kelić, S., Gross, C., Xu, M., & Bassell, G. J. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.0937-07.2007 · Cited by 421
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BK Channels in the Central Nervous System
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Metadata
- Authors
- Myrick, L. K., Deng, P.-Y., Hashimoto, H., Oh, Y. M., Cho, Y., Poidevin, M. J., Suhl, J. A., Visootsak, J., Cavalli, V., Jin, P., Cheng, X., Warren, S. T., & Klyachko, V. A.
- Affiliations
- Emory University (US)
- Departments of bBiomedical Engineering and Cell Biology and Physiology and
- Washington University in St. Louis (US)
- Departments of aHuman Genetics,
- Biochemistry, and
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-01-05
- Volume
- 112
- Issue
- 4
- Pages
- 949-956
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4313821
- OpenAlex
- W1979762144
- Cited by
- 133
- References
- 56
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 8 · 2023: 7 · 2022: 8 · 2021: 11 · 2020: 8 · 2019: 14 · 2018: 18 · 2017: 14 · 2016: 13 · 2015: 13
- FWCI
- 13.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Neurological Disorders and Stroke (1U54NS091859, NS089449)
- HHS | NIH | National Institute of General Medical Sciences (GM049245)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Keywords
- FMRP, FMR1 gene, fragile X syndrome, presynaptic function, missense mutations, intellectual disability, seizures, neuromuscular junction, action potential broadening, BK channels, translational regulation, RNA binding, Drosophila, Fmr1 knockout mice
- MeSH terms
- Action Potentials, Animals, Child, Child, Preschool, Drosophila, Fragile X Syndrome, Gene Expression Regulation, Humans, Male, Seizures, Amino Acid Substitution, Mutation, Missense, Mice, Fragile X Messenger Ribonucleoprotein 1
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