Toward Fulfilling the Promise of Molecular Medicine in Fragile X Syndrome
Open accessAbstract
Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading known cause of autism. It is caused by loss of expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein that negatively regulates protein synthesis. In neurons, multiple lines of evidence suggest that protein synthesis at synapses is triggered by activation of group 1 metabotropic glutamate receptors (Gp1 mGluRs) and that many functional consequences of activating these receptors are altered in the absence of FMRP. These observations have led to the theory that exaggerated protein synthesis downstream of Gp1 mGluRs is a core pathogenic mechanism in FXS. This excess can be corrected by reducing signaling by Gp1 mGluRs, and numerous studies have shown that inhibition of mGluR5, in particular, can ameliorate multiple mutant phenotypes in animal models of FXS. Clinical trials based on this therapeutic strategy are currently under way. FXS is therefore poised to be the first neurobehavioral disorder in which corrective treatments have been developed from the bottom up: from gene identification to pathophysiology in animals to novel therapeutics in humans. The insights gained from FXS and other autism-related single-gene disorders may also assist in identifying molecular mechanisms and potential treatment approaches for idiopathic autism.
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Elevated mGluR5-mediated signaling and protein synthesis in fragile X knockout mice provided the rationale for testing mGluR5 antagonists in fragile X clinical trials.
“Discovery of elevated metabotropic glutamate receptor subtype 5 (mGluR5)–mediated signaling and protein synthesis in fragile X knockout mice (53–56) provided the rationale for testing mGluR5 antagonists in ongoing fragile X clinical trials.”
From Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism (2012) · cites this paper as [55]
Early clinical indications of beneficial actions of mGluR5 antagonists in fragile X syndrome make this class of therapeutic targets of particular interest.
“Early clinical indications of beneficial actions of mGluR5 antagonists in fragile X syndrome make this class of therapeutic targets of particular interest (55).”
From Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism (2012) · cites this paper as [55]
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- Authors
- Krueger, D. D., & Bear, M. F.
- Affiliations
- The Picower Institute for Learning and Memory, Howard Hughes Medical Institute, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139;
- Howard Hughes Medical Institute (US)
- ORCID
- Bear, Mark F.
- Venue
- Annual Review of Medicine
- Publisher
- Annual Reviews
- Published
- 2011-02-18
- Volume
- 62
- Issue
- 1
- Pages
- 411-429
- ISSN
- 0066-4219 (ISSN-L)
- 1545-326X
- PMC
- PMC3100156
- OpenAlex
- W2162507760
- Cited by
- 259
- References
- 101
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2022: 8 · 2021: 11 · 2020: 13 · 2019: 3 · 2018: 5 · 2017: 14 · 2016: 12 · 2015: 27 · 2014: 38 · 2013: 38 · 2012: 61
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annual Review of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Foundation for the National Institutes of Health
- Howard Hughes Medical Institute
- FRAXA Research Foundation
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD046943)
- 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 › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- fragile X syndrome, FMRP, group I metabotropic glutamate receptors, mGluR5, synaptic protein synthesis, autism spectrum disorder, intellectual disability, mGluR5 antagonist, autism treatment, idiopathic autism
- MeSH terms
- Animals, Autistic Disorder, Clinical Trials as Topic, Fragile X Syndrome, Humans, Neurofibromatosis 1, Neuronal Plasticity, Tuberous Sclerosis, Rett Syndrome, Receptors, Metabotropic Glutamate, PTEN Phosphohydrolase, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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