An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors
| Autor: | Nashaat Z. Gerges, Reem Jada, Reut Shalgi, Megha Sah, Eli Rogers, Daniela Lichtman, Rachel E. Moss, Matthew A. Florence, George K.E. Umanah, Marisol Cortes, Nina S. Levy, Itamar Kahn, Alexandra Kavushansky, Randall S. Walikonis, Raz Palty, Kinneret Schragenheim-Rozales, Andrew P. Levy |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
calmodulin Mutant autism Hippocampus AMPA receptor Hippocampal formation Biology lcsh:RC321-571 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine AMPA IQSEC2 medicine Arf6 GEF lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Molecular Biology Original Research IQ domain Wild type medicine.disease 3. Good health 030104 developmental biology intellectual disability Mutation (genetic algorithm) Cancer research Autism Guanine nucleotide exchange factor 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | Frontiers in Molecular Neuroscience, Vol 12 (2019) Frontiers in Molecular Neuroscience |
| ISSN: | 1662-5099 |
| Popis: | We have recently described an A350V mutation in IQSEC2 associated with intellectual disability, autism and epilepsy. We sought to understand the molecular pathophysiology of this mutation with the goal of developing targets for drug intervention. We demonstrate here that the A350V mutation results in interference with the binding of apocalmodulin to the IQ domain of IQSEC2. We further demonstrate that this mutation results in constitutive activation of the guanine nucleotide exchange factor (GEF) activity of IQSEC2 resulting in increased production of the active form of Arf6. In a CRISPR generated mouse model of the A350V IQSEC2 mutation, we demonstrate that the surface expression of GluA2 AMPA receptors in mouse hippocampal tissue was significantly reduced in A350V IQSEC2 mutant mice compared to wild type IQSEC2 mice and that there is a significant reduction in basal synaptic transmission in the hippocampus of A350V IQSEC2 mice compared to wild type IQSEC2 mice. Finally, the A350V IQSEC2 mice demonstrated increased activity, abnormal social behavior and learning as compared to wild type IQSEC2 mice. These findings suggest a model of how the A350V mutation in IQSEC2 may mediate disease with implications for targets for drug therapy. These studies provide a paradigm for a personalized approach to precision therapy for a disease that heretofore has no therapy. |
| Databáze: | OpenAIRE |
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