Correction of Fragile X Syndrome in Mice

Dölen, Gül; Osterweil, Emily K.; Rao, B.S. Shankaranarayana; Smith, Gordon B.; Auerbach, Benjamin D.; Chattarji, Sumantra; Bear, Mark F.

doi:10.1016/j.neuron.2007.12.001

Cited by 891 publications

(940 citation statements)

References 36 publications

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“…Animal models of fragile X syndrome with heterozygous knockout of the mGluR5 receptor suggest phenotypic rescue of many of the features of fragile X, including increased risk for seizures. 30 These studies demonstrate a clear role for the FMR1 gene in seizures. However, whether the observed increased gene dosage of the FMR1 could also lead to the seizure activity seen in our patient is not clear.…”

Section: Discussionmentioning

confidence: 74%

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

et al. 2012

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Loss-of-function due to expansion of a CGG repeat located in the 5'UTR of the FMR1 gene is the most frequent cause of fragile X syndrome. Less than 1% of individuals with fragile X syndrome have been reported to have a partial or full deletion or point mutation of the FMR1 gene. However, whether a copy number gain of the FMR1 gene could result in certain clinical phenotypes has not been fully investigated. Here, we report the case of a child who presented with developmental delay starting at 9 months of age, fine motor and speech delay, progressive seizures since 18 months of age and hyperactivity. Molecular workup identified a de novo microduplication in the Xq27.3 region, including the FMR1 gene and the ASFMR1 gene. The expression level of the FMR1 gene in peripheral blood did not differ from that of the controls. In addition, an inherited 363-kb duplication on the chromosome 1q44 region and an inherited deletion of 168 kb on the chromosome 4p15.31 region were detected. It is not clear whether these inherited copy number variations (CNVs) also have a modifying role in the clinical phenotype of this patient.

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Section: Discussionmentioning

confidence: 74%

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

et al. 2012

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“…Abnormalities in mGlu5 signaling in the hippocampus have been reported in several models of ASDs, in particular the FMR1 KO model and mGlu5 antagonist reverse molecular and behavioral deficits in FMR1 knockout mice, and have also been tested in clinical trials for fragile-X patients, with some promising results (Dölen et al, 2007(Dölen et al, , 2010Jacquemont et al, 2011). Our data demonstrate that GluD1 is an important regulator of mGlu5 signaling and protein synthesis, and further analysis of the roles of GluD1 is necessary to fully understand its contribution to central nervous system physiology and neuropsychiatric disorders.…”

Section: Discussionmentioning

confidence: 99%

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

et al. 2016

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The delta family of ionotropic glutamate receptors consists of glutamate delta-1 (GluD1) and glutamate delta-2 receptors. We have previously shown that GluD1 knockout mice exhibit features of developmental delay, including impaired spine pruning and switch in the N-methyl-D-aspartate receptor subunit, which are relevant to autism and other neurodevelopmental disorders. Here, we identified a novel role of GluD1 in regulating metabotropic glutamate receptor 5 (mGlu5) signaling in the hippocampus. Immunohistochemical analysis demonstrated colocalization of mGlu5 with GluD1 punctas in the hippocampus. Additionally, GluD1 protein coimmunoprecipitated with mGlu5 in the hippocampal membrane fraction, as well as when overexpressed in human embryonic kidney 293 cells, demonstrating that GluD1 and mGlu5 may cooperate in a signaling complex. The interaction of mGlu5 with scaffold protein effector Homer, which regulates mechanistic target of rapamycin (mTOR) signaling, was abnormal both under basal conditions and in response to mGlu1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) in GluD1 knockout mice. The basal levels of phosphorylated mTOR and protein kinase B, the signaling proteins downstream of mGlu5 activation, were higher in GluD1 knockout mice, and no further increase was induced by DHPG. We also observed higher basal protein translation and an absence of DHPG-induced increase in GluD1 knockout mice. In accordance with a role of mGlu5-mediated mTOR signaling in synaptic plasticity, DHPG-induced internalization of surface a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits was impaired in the GluD1 knockout mice. These results demonstrate that GluD1 interacts with mGlu5, and loss of GluD1 impairs normal mGlu5 signaling potentially by dysregulating coupling to its effector. These studies identify a novel role of the enigmatic GluD1 subunit in hippocampal function.

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“…This decrease is due to excessive mGluR5 signaling resulting in an increased Arc translation and consequently excessive AMPA receptors internalization (Dolen & Bear, 2008). In FMR1 knockout mice, injections of mGluR5 restore the AMPA receptors expression levels and prevent fragile X syndrome (Dolen et al., 2007). …”

Section: Reviewmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.MethodsA narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ResultsGenome‐wide linkages, association studies, and genetic analyses of patients with ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.ConclusionThis review describes the genetic aspects of ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.

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Correction of Fragile X Syndrome in Mice

Cited by 891 publications

References 36 publications

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

Autism throughout genetics: Perusal of the implication of ion channels

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