An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors
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 i...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-02-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnmol.2019.00043/full |
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| author | Eli J. Rogers Reem Jada Kinneret Schragenheim-Rozales Megha Sah Marisol Cortes Matthew Florence Nina S. Levy Rachel Moss Randall S. Walikonis Raz Palty Reut Shalgi Daniela Lichtman Alexandra Kavushansky Nashaat Z. Gerges Itamar Kahn George K. E. Umanah Andrew P. Levy |
| author_facet | Eli J. Rogers Reem Jada Kinneret Schragenheim-Rozales Megha Sah Marisol Cortes Matthew Florence Nina S. Levy Rachel Moss Randall S. Walikonis Raz Palty Reut Shalgi Daniela Lichtman Alexandra Kavushansky Nashaat Z. Gerges Itamar Kahn George K. E. Umanah Andrew P. Levy |
| author_sort | Eli J. Rogers |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T00:35:36Z |
| format | Article |
| id | doaj.art-14ef286995ec4aa7b07fafd45f233f65 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-23T00:35:36Z |
| publishDate | 2019-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-14ef286995ec4aa7b07fafd45f233f652022-12-21T18:06:47ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992019-02-011210.3389/fnmol.2019.00043433262An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA ReceptorsEli J. Rogers0Reem Jada1Kinneret Schragenheim-Rozales2Megha Sah3Marisol Cortes4Matthew Florence5Nina S. Levy6Rachel Moss7Randall S. Walikonis8Raz Palty9Reut Shalgi10Daniela Lichtman11Alexandra Kavushansky12Nashaat Z. Gerges13Itamar Kahn14George K. E. Umanah15Andrew P. Levy16Technion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelTechnion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelTechnion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelDepartment of Physiology and Neurobiology, University of Connecticut, Storrs, CT, United StatesDepartment of Neurology, Johns Hopkins University, Baltimore, MD, United StatesDepartment of Biopharmaceutical Sciences and Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United StatesTechnion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelTechnion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelDepartment of Physiology and Neurobiology, University of Connecticut, Storrs, CT, United StatesTechnion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelTechnion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelTechnion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelTechnion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelDepartment of Biopharmaceutical Sciences and Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United StatesTechnion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelDepartment of Neurology, Johns Hopkins University, Baltimore, MD, United StatesTechnion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelWe 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.https://www.frontiersin.org/article/10.3389/fnmol.2019.00043/fullIQSEC2Arf6GEFAMPAcalmodulinIQ domain |
| spellingShingle | Eli J. Rogers Reem Jada Kinneret Schragenheim-Rozales Megha Sah Marisol Cortes Matthew Florence Nina S. Levy Rachel Moss Randall S. Walikonis Raz Palty Reut Shalgi Daniela Lichtman Alexandra Kavushansky Nashaat Z. Gerges Itamar Kahn George K. E. Umanah Andrew P. Levy An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors Frontiers in Molecular Neuroscience IQSEC2 Arf6 GEF AMPA calmodulin IQ domain |
| title | An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors |
| title_full | An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors |
| title_fullStr | An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors |
| title_full_unstemmed | An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors |
| title_short | An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors |
| title_sort | iqsec2 mutation associated with intellectual disability and autism results in decreased surface ampa receptors |
| topic | IQSEC2 Arf6 GEF AMPA calmodulin IQ domain |
| url | https://www.frontiersin.org/article/10.3389/fnmol.2019.00043/full |
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