Cited by 133Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchDown syndrome and intellectual disability research

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Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

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Myrick, Leila K., Deng, Pan-Yue, Hashimoto, Hideharu, Oh, Young Mi, Cho, Yongcheol, Poidevin, Mickael J., Suhl, Joshua A., Visootsak, Jeannie, Cavalli, Valeria, Jin, Peng, Cheng, Xiaodong, Warren, Stephen T., Klyachko, Vitaly A.·2015·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1423094112PMC PMC4313821

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Abstract

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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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: Myrick, Leila K.
Deng, Pan-Yue
Hashimoto, Hideharu
Oh, Young Mi
Cho, Yongcheol
Visootsak, Jeannie
Cavalli, Valeria
Jin, Peng
Cheng, Xiaodong
Warren, Stephen T.
Klyachko, Vitaly A.
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
DOI: 10.1073/pnas.1423094112
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
Licence: www.pnas.org/site/misc/userlicense.xhtml (vor, 181 d)
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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Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

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