ArticleThe Journal of biological chemistry2015
Lipid binding defects and perturbed synaptogenic activity of a Collybistin R290H mutant that causes epilepsy and intellectual disability.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 37 citations in OpenAlex.
- Autism-associated ARHGEF9 variants impair GABAergic synapses and ultrasonic communication by reducing gephyrin phosphorylation.Molecular psychiatry · 2026Article
- Impaired axon initial segment structure and function in a model ofProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Epileptiform activity influences theta-burst induced LTP in the adult hippocampus: a role for synaptic lipid raft disruption in early metaplasticity?Frontiers in cellular neuroscience · 2023Article
- In vitro fluorescence assay to measure GDP/GTP exchange of guanine nucleotide exchange factors of Rho family GTPases.Biology methods & protocols · 2022Article
- Neuroligin-2 dependent conformational activation of collybistin reconstituted in supported hybrid membranes.The Journal of biological chemistry · 2020Article
- Clinical and Molecular Characterization of Three Novel ARHGEF9 Mutations in Patients with Developmental Delay and Epilepsy.Journal of molecular neuroscience : MN · 2020Article
- Identification of a Core Amino Acid Motif within the α Subunit of GABACell reports · 2019Article
- Intracellular pH dynamics and charge-changing somatic mutations in cancer.Cancer metastasis reviews · 2019Review
- Mutation p.R356Q in the Collybistin Phosphoinositide Binding Site Is Associated With Mild Intellectual Disability.Frontiers in molecular neuroscience · 2019Article
- Biochemical and Morphological Characterization of a Guanine Nucleotide Exchange Factor ARHGEF9 in Mouse Tissues.Acta histochemica et cytochemica · 2018Article
- Critical roles of αII spectrin in brain development and epileptic encephalopathy.The Journal of clinical investigation · 2018Article
- ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation.Neurogenetics · 2018Article
- Synaptic Plasticity and Excitation-Inhibition Balance in the Dentate Gyrus: Insights fromNeural plasticity · 2018Review
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- In vivo transgenic expression of collybistin in neurons of the rat cerebral cortex.The Journal of comparative neurology · 2017Article
- Endosomal Phosphatidylinositol 3-Phosphate Promotes Gephyrin Clustering and GABAergic Neurotransmission at Inhibitory Postsynapses.The Journal of biological chemistry · 2017Article
- TRIM31 promotes Atg5/Atg7-independent autophagy in intestinal cells.Nature communications · 2016Article
- Specificity of Collybistin-Phosphoinositide Interactions: IMPACT OF THE INDIVIDUAL PROTEIN DOMAINS.The Journal of biological chemistry · 2016Article
- Missense Mutation R338W in ARHGEF9 in a Family with X-linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism.Frontiers in molecular neuroscience · 2015Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Signaling at nerve cell synapses is a key determinant of proper brain function, and synaptic defects--or synaptopathies--are at the basis of many neurological and psychiatric disorders. In key areas of the mammalian brain, such as the hippocampus or the basolateral amygdala, the clustering of the scaffolding protein Gephyrin and of γ-aminobutyric acid type A receptors at inhibitory neuronal synapses is critically dependent upon the brain-specific guanine nucleotide exchange factor Collybistin (Cb). Accordingly, it was discovered recently that an R290H missense mutation in the diffuse B-cell lymphoma homology domain of Cb, which carries the guanine nucleotide exchange factor activity, leads to epilepsy and intellectual disability in human patients. In the present study, we determined the mechanism by which the Cb(R290H) mutation perturbs inhibitory synapse formation and causes brain dysfunction. Based on a combination of biochemical, cell biological, and molecular dynamics simulation approaches, we demonstrate that the R290H mutation alters the strength of intramolecular interactions between the diffuse B-cell lymphoma homology domain and the pleckstrin homology domain of Cb. This defect reduces the phosphatidylinositol 3-phosphate binding affinity of Cb, which limits its normal synaptogenic activity. Our data indicate that impairment of the membrane lipid binding activity of Cb and a consequent defect in inhibitory synapse maturation represent a likely molecular pathomechanism of epilepsy and mental retardation in humans.
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