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The molecular biology of FMRP: new insights into fragile X syndrome

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Richter, Joel D., Zhao, Xinyu·2021·Nature Reviews Neuroscience
DOI 10.1038/s41583-021-00432-0PMC PMC8094212
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Abstract

Fragile X mental retardation protein (FMRP) is the product of the fragile X mental retardation 1 gene (FMR1), a gene that - when epigenetically inactivated by a triplet nucleotide repeat expansion - causes the neurodevelopmental disorder fragile X syndrome (FXS). FMRP is a widely expressed RNA-binding protein with activity that is essential for proper synaptic plasticity and architecture, aspects of neural function that are known to go awry in FXS. Although the neurophysiology of FXS has been described in remarkable detail, research focusing on the molecular biology of FMRP has only scratched the surface. For more than two decades, FMRP has been well established as a translational repressor; however, recent whole transcriptome and translatome analyses in mouse and human models of FXS have shown that FMRP is involved in the regulation of nearly all aspects of gene expression. The emerging mechanistic details of the mechanisms by which FMRP regulates gene expression may offer ways to design new therapies for FXS.

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  • FXS is caused by the absence of FMRP, which is essential for normal synapse formation and plasticity.

    “FXS is caused by the absence of Fragile X messenger ribonucleoprotein (FMRP) which is essential for normal synapse formation and plasticity13.”

    From An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis (2023) · cites this paper as [13]

    The Introduction (page unavailable) says that nearly all FXS cases involve FMR1 silencing and loss of FMRP, and that FMR1 inactivation impairs dendrite morphogenesis and circuit integration. A section on translation initiation also links FMRP-related processes to dendritic spine morphogenesis. Those non-abstract passages support the cause and synapse-formation aspects, but do not establish the claim about normal synaptic plasticity. (LLM, conf=0.76)

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Authors
Richter, J. D., & Zhao, X.
Affiliations
  • University of Massachusetts Chan Medical School (US)
  • University of Wisconsin–Madison (US)
Corresponding author
  • Richter, Joel D.
  • Zhao, Xinyu
ORCID
Venue
Nature Reviews Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2021-02-19
Volume
22
Issue
4
Pages
209-222
ISSN
  • 1471-003X (ISSN-L)
  • 1471-0048
DOI
10.1038/s41583-021-00432-0
PMC
PMC8094212
OpenAlex
W3131228145
Cited by
390
References
18
Citations by year
2026: 53 · 2025: 90 · 2024: 87 · 2023: 73 · 2022: 61 · 2021: 25
FWCI
9.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
Funders
  • National Institute of Mental Health (R01MH118827, R01MH116582)
  • National Institute of General Medical Sciences (R01GM046779, R01GM135087)
  • National Institute of Neurological Disorders and Stroke (R21NS105339, R01NS105200)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090256, U54HD082013)
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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
FMRP, fragile X syndrome, FMR1 gene, RNA-binding proteins, protein synthesis inhibition, translatome, gene expression regulation, trinucleotide repeat expansion, synaptic plasticity, neurodevelopmental disorders
MeSH terms
Animals, Fragile X Syndrome, Humans, Neuronal Plasticity, Neurons, Trinucleotide Repeat Expansion, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1

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