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1. Biochemical autoregulatory gene therapy for focal epilepsy

Author

Lieb, Andreas, Qiu, Yichen, Dixon, Christine L., Heller, Janosch P., Walker, Matthew C., Schorge, Stephanie, and Kullmann, Dimitri M.

Subjects
Gene therapy -- Usage -- Research, Rodents -- Models -- Genetic aspects, Epilepsy -- Care and treatment -- Genetic aspects -- Models -- Research, Neurons, Genes, Glutamate, Genetic vectors, Seizures (Medicine), Biological sciences, Health
Abstract

Despite the introduction of more than one dozen new antiepileptic drugs in the past 20 years, approximately one-third of people who develop epilepsy continue to have seizures on mono- or polytherapy.sup.1. Viral-vector-mediated gene transfer offers the opportunity to design a rational treatment that builds on mechanistic understanding of seizure generation and that can be targeted to specific neuronal populations in epileptogenic foci.sup.2. Several such strategies have shown encouraging results in different animal models, although clinical translation is limited by possible effects on circuits underlying cognitive, mnemonic, sensory or motor function. Here, we describe an autoregulatory antiepileptic gene therapy, which relies on neuronal inhibition in response to elevations in extracellular glutamate. It is effective in a rodent model of focal epilepsy and is well tolerated, thus lowering the barrier to clinical translation. A glutamate-gated chloride channel delivered via gene therapy is shown to detect elevated brain glutamate levels and trigger the suppression of neuronal excitability, thereby attenuating seizure activity in two rodent models of epilepsy., Author(s): Andreas Lieb [sup.1] , Yichen Qiu [sup.1] , Christine L. Dixon [sup.1] , Janosch P. Heller [sup.1] , Matthew C. Walker [sup.1] , Stephanie Schorge [sup.1] , Dimitri M. [...]

Published
2018
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2. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Salpietro, Vincenzo, Dixon, Christine L., Guo, Hui, Bello, Oscar D., Vandrovcova, Jana, Efthymiou, Stephanie, Maroofian, Reza, Heimer, Gali, Burglen, Lydie, Valence, Stephanie, Torti, Erin, Hacke, Moritz, Rankin, Julia, Tariq, Huma, Colin, Estelle, Procaccio, Vincent, Striano, Pasquale, Mankad, Kshitij, Lieb, Andreas, Chen, Sharon, Pisani, Laura, Bettencourt, Conceicao, Männikkö, Roope, Manole, Andreea, Brusco, Alfredo, Grosso, Enrico, Ferrero, Giovanni Battista, Armstrong-Moron, Judith, Gueden, Sophie, Bar-Yosef, Omer, Tzadok, Michal, Monaghan, Kristin G., Santiago-Sim, Teresa, Person, Richard E., Cho, Megan T., Willaert, Rebecca, Yoo, Yongjin, Chae, Jong-Hee, Quan, Yingting, Wu, Huidan, Wang, Tianyun, Bernier, Raphael A., Xia, Kun, Blesson, Alyssa, Jain, Mahim, Motazacker, Mohammad M., Jaeger, Bregje, Schneider, Amy L., Boysen, Katja, Muir, Alison M., Myers, Candace T., Gavrilova, Ralitza H., Gunderson, Lauren, Schultz-Rogers, Laura, Klee, Eric W., Dyment, David, Osmond, Matthew, Parellada, Mara, Llorente, Cloe, Gonzalez-Peñas, Javier, Carracedo, Angel, Van Haeringen, Arie, Ruivenkamp, Claudia, Nava, Caroline, Heron, Delphine, Nardello, Rosaria, Iacomino, Michele, Minetti, Carlo, Skabar, Aldo, Fabretto, Antonella, SYNAPS Study Group, Raspall-Chaure, Miquel, Chez, Michael, Tsai, Anne, Fassi, Emily, Shinawi, Marwan, Constantino, John N., De Zorzi, Rita, Fortuna, Sara, Kok, Fernando, Keren, Boris, Bonneau, Dominique, Choi, Murim, Benzeev, Bruria, Zara, Federico, Mefford, Heather C., Scheffer, Ingrid E., Clayton-Smith, Jill, Macaya, Alfons, Rothman, James E., Eichler, Evan E., Kullmann, Dimitri M., and Houlden, Henry

Published
2019
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6. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Salpietro Vincenzo, Dixon Christine L., Guo Hui, Bello Oscar D., Vandrovcova Jana, Efthymiou Stephanie, Maroofian Reza, Heimer Gali, Burglen Lydie, Valence Stephanie, Torti Erin, Hacke Moritz, Rankin Julia, Tariq Huma, Colin Estelle, Procaccio Vincent, Striano Pasquale, Mankad Kshitij, Lieb Andreas, Chen Sharon, Pisani Laura, Bettencourt Conceicao, Mannikko Roope, Manole Andreea, Brusco Alfredo, Grosso Enrico, Ferrero Giovanni Battista, Armstrong-Moron Judith, Gueden Sophie, Bar-Yosef Omer, Tzadok Michal, Monaghan Kristin G., Santiago-Sim Teresa, Person Richard E., Cho Megan T., Willaert Rebecca, Yoo Yongjin, Chae Jong-Hee, Quan Yingting, Wu Huidan, Wang Tianyun, Bernier Raphael A., Xia Kun, Blesson Alyssa, Jain Mahim, Motazacker Mohammad M., Jaeger Bregje, Schneider Amy L., Boysen Katja, Muir Alison M., Myers Candace T., Gavrilova Ralitza H., Gunderson Lauren, Schultz-Rogers Laura, Klee Eric W., Dyment David, Osmond Matthew, Parellada Mara, Llorente Cloe, Gonzalez-Penas Javier, Carracedo Angel, Van Haeringen Arie, Ruivenkamp Claudia, Nava Caroline, Heron Delphine, Nardello Rosaria, Iacomino Michele, Minetti Carlo, Skabar Aldo, Fabretto Antonella, Chez Michael, Tsai Anne, Fassi Emily, Shinawi Marwan, Constantino John N., De Zorzi Rita, Fortuna Sara, Kok Fernando, Keren Boris, Bonneau Dominique, Choi Murim, Benzeev Bruria, Zara Federico, Mefford Heather C., Scheffer Ingrid E., Clayton-Smith Jill, Macaya Alfons, Rothman James E., Eichler Evan E., Kullmann Dimitri M., Houlden Henry, Raspall-Chaure Miquel, Hanna Michael G., Bugiardini Enrico, Hostettler Isabel, O'Callaghan Benjamin, Khan Alaa, Cortese Andrea, O'Connor Emer, Yau Wai Y., Bourinaris Thomas, Kaiyrzhanov Rauan, Chelban Viorica, Madej Monika, Diana Maria C., Vari Maria S., Pedemonte Marina, Bruno Claudio, Balagura Ganna, Scala Marcello, Fiorillo Chiara, Nobili Lino, Malintan Nancy T., Zanetti Maria N., Krishnakumar Shyam S., Lignani Gabriele, Jepson James E. C., Broda Paolo, Baldassari Simona, Rossi Pia, Fruscione Floriana, Madia Francesca, Traverso Monica, De-Marco Patrizia, Perez-Duenas Belen, Munell Francina, Kriouile Yamna, El-Khorassani Mohamed, Karashova Blagovesta, Avdjieva Daniela, Kathom Hadil, Tincheva Radka, Van-Maldergem Lionel, Nachbauer Wolfgang, Boesch Sylvia, Gagliano Antonella, Amadori Elisabetta, Goraya Jatinder S., Sultan Tipu, Kirmani Salman, Ibrahim Shahnaz, Jan Farida, Mine, Jun, Banu Selina, Veggiotti Pierangelo, Zuccotti Gian V, Ferrari Michel D., Van Den Maagdenberg Arn M. J., Verrotti Alberto, Marseglia Gian L., Savasta Salvatore, Soler Miguel A., Scuderi Carmela, Borgione Eugenia, Chimenz Roberto, Gitto Eloisa, Dipasquale Valeria, Sallemi Alessia, Fusco Monica, Cuppari Caterina, Cutrupi Maria C., Ruggieri Martino, Cama Armando, Capra Valeria, Mencacci Niccolo E., Boles Richard, Gupta Neerja, Kabra Madhulika, Papacostas Savvas, Zamba-Papanicolaou Eleni, Dardiotis Efthymios, Maqbool Shazia, Rana Nuzhat, Atawneh Osama, Lim Shen Y., Shaikh Farooq, Koutsis George, Breza Marianthi, Coviello Domenico A., Dauvilliers Yves A., AlKhawaja Issam, AlKhawaja Mariam, Al-Mutairi Fuad, Stojkovic Tanya, Ferrucci Veronica, Zollo Massimo, Alkuraya Fowzan S., Kinali Maria, Sherifa Hamed, Benrhouma Hanene, Turki Ilhem B. Y., Tazir Meriem, Obeid Makram, Bakhtadze Sophia, Saadi Nebal W., Zaki Maha S., Triki Chahnez C., Benfenati Fabio, Gustincich Stefano, Kara Majdi, Belcastro Vincenzo, Specchio Nicola, Capovilla Giuseppe, Karimiani Ehsan G., Salih Ahmed M., Okubadejo Njideka U., Ojo Oluwadamilola O., Oshinaike Olajumoke O., Oguntunde Olapeju, Wahab Kolawole, Bello Abiodun H., Abubakar Sanni, Obiabo Yahaya, Nwazor Ernest, Ekenze Oluchi, Williams Uduak, Iyagba Alagoma, Taiwo Lolade, Komolafe Morenikeji, Senkevich Konstantin, Shashkin Chingiz, Zharkynbekova Nazira, Koneyev Kairgali, Manizha Ganieva, Isrofilov Maksud, Guliyeva Ulviyya, Salayev Kamran, Khachatryan Samson, Rossi Salvatore, Silvestri Gabriella, Haridy Nourelhoda, Ramenghi Luca A., Xiromerisiou Georgia, David Emanuele, Aguennouz Mhammed, Fidani Liana, Spanaki Cleanthe, Tucci Arianna, Salpietro Vincenzo, Dixon Christine L., Guo Hui, Bello Oscar D., Vandrovcova Jana, Efthymiou Stephanie, Maroofian Reza, Heimer Gali, Burglen Lydie, Valence Stephanie, Torti Erin, Hacke Moritz, Rankin Julia, Tariq Huma, Colin Estelle, Procaccio Vincent, Striano Pasquale, Mankad Kshitij, Lieb Andreas, Chen Sharon, Pisani Laura, Bettencourt Conceicao, Mannikko Roope, Manole Andreea, Brusco Alfredo, Grosso Enrico, Ferrero Giovanni Battista, Armstrong-Moron Judith, Gueden Sophie, Bar-Yosef Omer, Tzadok Michal, Monaghan Kristin G., Santiago-Sim Teresa, Person Richard E., Cho Megan T., Willaert Rebecca, Yoo Yongjin, Chae Jong-Hee, Quan Yingting, Wu Huidan, Wang Tianyun, Bernier Raphael A., Xia Kun, Blesson Alyssa, Jain Mahim, Motazacker Mohammad M., Jaeger Bregje, Schneider Amy L., Boysen Katja, Muir Alison M., Myers Candace T., Gavrilova Ralitza H., Gunderson Lauren, Schultz-Rogers Laura, Klee Eric W., Dyment David, Osmond Matthew, Parellada Mara, Llorente Cloe, Gonzalez-Penas Javier, Carracedo Angel, Van Haeringen Arie, Ruivenkamp Claudia, Nava Caroline, Heron Delphine, Nardello Rosaria, Iacomino Michele, Minetti Carlo, Skabar Aldo, Fabretto Antonella, Chez Michael, Tsai Anne, Fassi Emily, Shinawi Marwan, Constantino John N., De Zorzi Rita, Fortuna Sara, Kok Fernando, Keren Boris, Bonneau Dominique, Choi Murim, Benzeev Bruria, Zara Federico, Mefford Heather C., Scheffer Ingrid E., Clayton-Smith Jill, Macaya Alfons, Rothman James E., Eichler Evan E., Kullmann Dimitri M., Houlden Henry, Raspall-Chaure Miquel, Hanna Michael G., Bugiardini Enrico, Hostettler Isabel, O'Callaghan Benjamin, Khan Alaa, Cortese Andrea, O'Connor Emer, Yau Wai Y., Bourinaris Thomas, Kaiyrzhanov Rauan, Chelban Viorica, Madej Monika, Diana Maria C., Vari Maria S., Pedemonte Marina, Bruno Claudio, Balagura Ganna, Scala Marcello, Fiorillo Chiara, Nobili Lino, Malintan Nancy T., Zanetti Maria N., Krishnakumar Shyam S., Lignani Gabriele, Jepson James E. C., Broda Paolo, Baldassari Simona, Rossi Pia, Fruscione Floriana, Madia Francesca, Traverso Monica, De-Marco Patrizia, Perez-Duenas Belen, Munell Francina, Kriouile Yamna, El-Khorassani Mohamed, Karashova Blagovesta, Avdjieva Daniela, Kathom Hadil, Tincheva Radka, Van-Maldergem Lionel, Nachbauer Wolfgang, Boesch Sylvia, Gagliano Antonella, Amadori Elisabetta, Goraya Jatinder S., Sultan Tipu, Kirmani Salman, Ibrahim Shahnaz, Jan Farida, Mine, Jun, Banu Selina, Veggiotti Pierangelo, Zuccotti Gian V, Ferrari Michel D., Van Den Maagdenberg Arn M. J., Verrotti Alberto, Marseglia Gian L., Savasta Salvatore, Soler Miguel A., Scuderi Carmela, Borgione Eugenia, Chimenz Roberto, Gitto Eloisa, Dipasquale Valeria, Sallemi Alessia, Fusco Monica, Cuppari Caterina, Cutrupi Maria C., Ruggieri Martino, Cama Armando, Capra Valeria, Mencacci Niccolo E., Boles Richard, Gupta Neerja, Kabra Madhulika, Papacostas Savvas, Zamba-Papanicolaou Eleni, Dardiotis Efthymios, Maqbool Shazia, Rana Nuzhat, Atawneh Osama, Lim Shen Y., Shaikh Farooq, Koutsis George, Breza Marianthi, Coviello Domenico A., Dauvilliers Yves A., AlKhawaja Issam, AlKhawaja Mariam, Al-Mutairi Fuad, Stojkovic Tanya, Ferrucci Veronica, Zollo Massimo, Alkuraya Fowzan S., Kinali Maria, Sherifa Hamed, Benrhouma Hanene, Turki Ilhem B. Y., Tazir Meriem, Obeid Makram, Bakhtadze Sophia, Saadi Nebal W., Zaki Maha S., Triki Chahnez C., Benfenati Fabio, Gustincich Stefano, Kara Majdi, Belcastro Vincenzo, Specchio Nicola, Capovilla Giuseppe, Karimiani Ehsan G., Salih Ahmed M., Okubadejo Njideka U., Ojo Oluwadamilola O., Oshinaike Olajumoke O., Oguntunde Olapeju, Wahab Kolawole, Bello Abiodun H., Abubakar Sanni, Obiabo Yahaya, Nwazor Ernest, Ekenze Oluchi, Williams Uduak, Iyagba Alagoma, Taiwo Lolade, Komolafe Morenikeji, Senkevich Konstantin, Shashkin Chingiz, Zharkynbekova Nazira, Koneyev Kairgali, Manizha Ganieva, Isrofilov Maksud, Guliyeva Ulviyya, Salayev Kamran, Khachatryan Samson, Rossi Salvatore, Silvestri Gabriella, Haridy Nourelhoda, Ramenghi Luca A., Xiromerisiou Georgia, David Emanuele, Aguennouz Mhammed, Fidani Liana, Spanaki Cleanthe, and Tucci Arianna

Published
2019

8. Loss of Frrs1l disrupts synaptic AMPA receptor function, and results in neurodevelopmental, motor, cognitive and electrographical abnormalities

Author

Stewart, Michelle, primary, Lau, Petrina, additional, Banks, Gareth, additional, Bains, Rasneer Sonia, additional, Castroflorio, Enrico, additional, Oliver, Peter L., additional, Dixon, Christine L., additional, Kruer, Michael C., additional, Kullmann, Dimitri M., additional, Acevedo-Arozena, Abraham, additional, Wells, Sara E., additional, Corrochano, Silvia, additional, and Nolan, Patrick M., additional

Published
2019
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9. Loss of Frrs1l disrupts synaptic AMPA receptor function, and results in neurodevelopmental, motor, cognitive and electrographical abnormalities

Author

Stewart, Michelle, primary, Lau, Petrina, additional, Banks, Gareth, additional, Bains, Rasneer Sonia, additional, Castroflorio, Enrico, additional, Oliver, Peter L., additional, Dixon, Christine L., additional, Kruer, Michael C., additional, Kullmann, Dimitri M., additional, Acevedo-Arozena, Abraham, additional, Wells, Sara E., additional, Corrochano, Silvia, additional, and Nolan, Patrick M., additional

Published
2018
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13. SAHA (Vorinostat) Corrects Inhibitory Synaptic Deficits Caused by Missense Epilepsy Mutations to the GABAA Receptor γ2 Subunit.

Author

Durisic, Nela, Keramidas, Angelo, Dixon, Christine L., and Lynch, Joseph W.

Subjects
GABA receptors, EPILEPSY, HYDROXAMIC acid derivatives
Abstract

The GABAA receptor (GABAAR) α1 subunit A295D epilepsy mutation reduces the surface expression of α1A295Dβ2γ2 GABAARs via ER-associated protein degradation. Suberanilohydroxamic acid (SAHA, also known as Vorinostat) was recently shown to correct the misfolding of α1A295D subunits and thereby enhance the functional surface expression of α1A295Dβ2γ2 GABAARs. Here we investigated whether SAHA can also restore the surface expression of γ2 GABAAR subunits that incorporate epilepsy mutations (N40S, R43Q, P44S, R138G) known to reduce surface expression via ER-associated protein degradation. As a control, we also investigated the γ2K289M epilepsy mutation that impairs gating without reducing surface expression. Effects of mutations were evaluated on inhibitory postsynaptic currents (IPSCs) mediated by the major synaptic α1β2γ2 GABAAR isoform. Recordings were performed in neuron-HEK293 cell artificial synapses to minimise contamination by GABAARs of undefined subunit composition. Transfection with α1β2γ2N40S, α1β2γ2R43Q, α1β2γ2P44S and α1β2γ2R138G subunits produced IPSCs with decay times slower than those of unmutated α1β2γ2 GABAARs due to the low expression of mutant γ2 subunits and the correspondingly high expression of slow-decaying α1β2 GABAARs. SAHA pre-treatment significantly accelerated the decay time constants of IPSCs consistent with the upregulation of mutant γ2 subunit expression. This increase in surface expression was confirmed by immunohistochemistry. SAHA had no effect on either the IPSC kinetics or surface expression levels of α1β2γ2K289M GABAARs, confirming its specificity for ER-retained mutant γ2 subunits. We also found that α1β2γ2K289M GABAARs and SAHA-treated α1β2γ2R43Q, α1β2γ2P44S and α1β2γ2R138G GABAARs all mediated IPSCs that decayed at significantly faster rates than wild type receptors as temperature was increased from 22 to 40°C. This may help explain why these mutations cause febrile seizures (FS). Given that SAHA is approved by therapeutic regulatory agencies for human use, we propose that it may be worth investigating as a treatment for epilepsies caused by the N40S, R43Q, P44S and R138G mutations. Although SAHA has already been proposed as a therapeutic for patients harbouring the α1A295D epilepsy mutation, the present study extends its potential utility to a new subunit and four new mutations. [ABSTRACT FROM AUTHOR]

Published
2018
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17. Pharmacological profile of essential oils derived from Lavandula angustifolia and Melissa officinalis with anti-agitation properties: focus on ligand-gated channels

Author

Huang, Liping, primary, Abuhamdah, Sawsan, additional, Howes, Melanie-Jayne R, additional, Dixon, Christine L, additional, Elliot, Mark S. J, additional, Ballard, Clive, additional, Holmes, Clive, additional, Burns, Alistair, additional, Perry, Elaine K, additional, Francis, Paul T, additional, Lees, George, additional, and Chazot, Paul L, additional

Published
2009
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18. Zolpidem and eszopiclone prime α1β2γ2 GABAA receptors for longer duration of activity.

Author

Dixon, Christine L, Harrison, Neil L, Lynch, Joseph W, and Keramidas, Angelo

Subjects
*ZOLPIDEM, *LUNESTA (Drug), *GABA receptors, *BRAIN physiology, *BENZODIAZEPINES
Abstract

Background and Purpose GABAA receptors mediate neuronal inhibition in the brain. They are the primary targets for benzodiazepines, which are widely used to treat neurological disorders including anxiety, epilepsy and insomnia. The mechanism by which benzodiazepines enhance GABAA receptor activity has been extensively studied, but there is little mechanistic information on how non-benzodiazepine drugs that bind to the same site exert their effects. Eszopiclone and zolpidem are two non-benzodiazepine drugs for which no mechanism of action has yet been proposed, despite their clinical importance as sleeping aids. Here we investigate how both drugs enhance the activity of α1β2γ2 GABAA receptors. Experimental Approach We used rapid ligand application onto macropatches and single-channel kinetic analysis to assess rates of current deactivation. We also studied synaptic currents in primary neuronal cultures and in heterosynapses, whereby native GABAergic nerve terminals form synapses with HEK293 cells expressing α1β2γ2 GABAA receptors. Drug binding and modulation was quantified with the aid of an activation mechanism. Key Results At the single-channel level, the drugs prolonged the duration of receptor activation, with similar KD values of ∼80 nM. Channel activation was prolonged primarily by increasing the equilibrium constant between two connected shut states that precede channel opening. Conclusions and Implications As the derived mechanism successfully simulated the effects of eszopiclone and zolpidem on ensemble currents, we propose it as the definitive mechanism accounting for the effects of both drugs. Importantly, eszopiclone and zolpidem enhanced GABAA receptor currents via a mechanism that differs from that proposed for benzodiazepines. [ABSTRACT FROM AUTHOR]

Published
2015
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19. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Salpietro, Vincenzo, Dixon, Christine L, Guo, Hui, Bello, Oscar D, Vandrovcova, Jana, Efthymiou, Stephanie, Raspall Chaure, Miquel, Macaya Ruíz, Alfons, Institut Català de la Salut, [Salpietro V] Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK. Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto 'Giannina Gaslini', Genoa, Italy. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy. [Dixon CL, Bello OD] Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. [Guo H] Department of Genome Sciences, University of Washington School of Medicine, Seattle, USA. Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China. [Vandrovcova J] Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK. [Efthymiou S] Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. [Raspall-Chaure M, Macaya A] Servei de Neurologia Pediatrica, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain., Hospital Universitari Vall d'Hebron, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Trastornos Mentales::Trastornos del Neurodesarrollo [PSIQUIATRÍA Y PSICOLOGÍA], Otros calificadores::Otros calificadores::/genética [Otros calificadores], trastornos mentales::trastornos del desarrollo neurológico [PSIQUIATRÍA Y PSICOLOGÍA], Mutació (Biologia), Proteïnes de membrana, Other subheadings::Other subheadings::/genetics [Other subheadings], Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES], Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Membrane Transport Proteins::Ion Channels::Ligand-Gated Ion Channels::Receptors, Ionotropic Glutamate::Receptors, AMPA [CHEMICALS AND DRUGS], Trastorns del desenvolupament - Aspectes genètics, Aminoácidos, Péptidos y Proteínas::Proteínas::Proteínas Portadoras::Proteínas de Transporte de Membrana::Canales Iónicos::Canales Iónicos Activados por Ligandos::Receptores Ionotrópicos de Glutamato::Receptores AMPA [COMPUESTOS QUÍMICOS Y DROGAS], fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS], aminoácidos, péptidos y proteínas::proteínas::proteínas transportadoras::proteínas de transporte de membrana::canales iónicos::canales iónicos de apertura por ligandos::receptores ionotrópicos de glutamato::receptores AMPA [COMPUESTOS QUÍMICOS Y DROGAS], Mental Disorders::Neurodevelopmental Disorders [PSYCHIATRY AND PSYCHOLOGY]
Abstract

Neurodevelopmental disorders; AMPA; GluA2 Trastorns del neurodesenvolupament; AMPA; GluA2 Trastornos del neurodesarrollo; AMPA; GluA2 AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission. Supported by the Wellcome Trust (WT093205MA and WT104033AIA), Medical Research Council (H.H. and D.M.K.), European Community’s Seventh Framework Programme (FP7/2007‐2013, under grant agreement No. 2012‐305121 to H.H.), Muscular Dystrophy Association (MDA), Muscular Dystrophy UK, The MSA Trust, Ataxia UK, The Sparkes Children’s Medical Research Charity, The Great Ormond Street Hospital Charity, Rosetrees Trust, Brain Research UK, The UK HSP Society, The European Union’s Horizon 2020 research and innovation programme Solve-RD project (No 779257), The Pakistan Council (Scholarship to HT), The National Natural Science Foundation of China (31671114, 81871079, 81330027, and 81525007 to H.G. and K.X.), the US National Institutes of Health (NIH grant R01MH101221 to E.E.E), the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) and the Biomedical Research Centre (BRC)

20. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Vincenzo Salpietro1, 2 3, 140, Christine L. Dixon4, Hui Guo5, 6 140, Oscar D. Bello Stephanie Efthymiou 1, 4, Reza Maroofian1, Gali Heimer7, Lydie Burglen 8, Stephanie Valence 9, Erin Torti 10, Moritz Hacke11, Julia Rankin12, Huma Tariq1, Estelle Colin13, Vincent Procaccio13, Pasquale Striano2, 3, Kshitij Mankad15, Andreas Lieb 4, Sharon Chen16, Laura Pisani16, Conceicao Bettencourt 17, Roope Männikkö 1, Andreea Manole1, Alfredo Brusco 18, Enrico Grosso18, Giovanni Battista Ferrero19, Judith Armstrong-Moron20, Sophie Gueden21, Omer Bar-Yosef7, Michal Tzadok7, Kristin G. Monaghan10, Teresa Santiago-Sim10, Richard E. Person10, Megan T. Cho10, Rebecca Willaert10, Yongjin Yoo22, Jong-Hee Chae23, Yingting Quan6, Huidan Wu6, Tianyun Wang5, 6, Raphael A. Bernier24, Kun Xia6, Alyssa Blesson25, Mahim Jain25, Mohammad M. Motazacker26, Bregje Jaeger27, Amy L. Schneider 28, Katja Boysen28, Alison M. Muir 29, Candace T. Myers30, Ralitza H. Gavrilova31, Lauren Gunderson31, Laura Schultz-Rogers 31, Eric W. Klee31, David Dyment32, Matthew Osmond32, 33 34, Mara Parellada35, Cloe Llorente36, Javier Gonzalez-Peñas37, Angel Carracedo38, Arie Van Haeringen40, Claudia Ruivenkamp40, Caroline Nava41, Delphine Heron41, Rosaria Nardello42, Michele Iacomino43, Carlo Minetti2, Aldo Skabar44, Antonella Fabretto44, SYNAPS Study GroupMiquel Raspall-Chaure45, Michael Chez46, Anne Tsai47, Emily Fassi48, Marwan Shinawi48, John N. Constantino49, Rita De Zorzi50, Sara Fortuna 50, Fernando Kok51, Boris Keren41, Dominique Bonneau13, Murim Choi 22, Bruria Benzeev7, Federico Zara43, Heather C. Mefford29, Ingrid E. Scheffer28, Jill Clayton-Smith53, Alfons Macaya45, James E. Rothman4, Evan E. Eichler 5, Dimitri M. Kullmann 4, Henry Houlden 1, SYNAPS Study Group Michael G. Hanna1, Enrico Bugiardini1, Isabel Hostettler1, Benjamin O’Callaghan1, Alaa Khan1, Andrea Cortese1, Emer O’Connor1, Wai Y. Yau1, Thomas Bourinaris1, Rauan Kaiyrzhanov1, Viorica Chelban1, Monika Madej1, Maria C. Diana2, Maria S. Vari2, Marina Pedemonte2, Claudio Bruno2, Ganna Balagura3, Marcello Scala3, Chiara Fiorillo3, Lino Nobili3, Nancy T. Malintan4, Maria N. Zanetti4, Shyam S. Krishnakumar4, Gabriele Lignani4, James E. C. Jepson4, Paolo Broda43, Simona Baldassari43, Pia Rossi43, Floriana Fruscione43, Francesca Madia43, Monica Traverso43, Patrizia De-Marco43, Belen Pérez-Dueñas45, Francina Munell45, Yamna Kriouile57, Mohamed El-Khorassani57, Blagovesta Karashova58, Daniela Avdjieva58, Hadil Kathom58, Radka Tincheva58, Lionel Van-Maldergem59, Wolfgang Nachbauer60, Sylvia Boesch60, Antonella Gagliano61, Elisabetta Amadori62, Jatinder S. Goraya63, Tipu Sultan64, Salman Kirmani65, Shahnaz Ibrahim66, Farida Jan66, Jun Mine67, Selina Banu68, Pierangelo Veggiotti69, Gian V. Zuccotti69, Michel D. Ferrari70, Arn M. J. Van Den Maagdenberg70, Alberto Verrotti71, Gian L. Marseglia72, Salvatore Savasta72, Miguel A. Soler73, Carmela Scuderi74, Eugenia Borgione74, Roberto Chimenz75, Eloisa Gitto75, Valeria Dipasquale75, Alessia Sallemi75, Monica Fusco75, Caterina Cuppari75, Maria C. Cutrupi75, Martino Ruggieri76, Armando Cama77, Valeria Capra77, Niccolò E. Mencacci78, Richard Boles79, Neerja Gupta80, Madhulika Kabra80, Savvas Papacostas81, Eleni Zamba-Papanicolaou81, Efthymios Dardiotis82, Shazia Maqbool83, Nuzhat Rana84, Osama Atawneh85, Shen Y. Lim86, Farooq Shaikh87, George Koutsis88, Marianthi Breza88, Domenico A. Coviello89, Yves A. Dauvilliers90, Issam AlKhawaja91, Mariam AlKhawaja92, Fuad Al-Mutairi93, Tanya Stojkovic94, Veronica Ferrucci, Massimo Zollo, Fowzan S. Alkuraya96, Maria Kinali97, Hamed Sherifa98, Hanene Benrhouma99, Ilhem B. Y. Turki99, Meriem Tazir100, Makram Obeid101, Sophia Bakhtadze102, Nebal W. Saadi103, Maha S. Zaki104, Chahnez C. Triki105, Fabio Benfenati106, Stefano Gustincich106, Majdi Kara107, Vincenzo Belcastro108, Nicola Specchio109, Giuseppe Capovilla110, Ehsan G. Karimiani111, Ahmed M. Salih112, Njideka U. Okubadejo113, Oluwadamilola O. Ojo113, Olajumoke O. Oshinaike113, Olapeju Oguntunde113, Kolawole Wahab114, Abiodun H. Bello114, Sanni Abubakar115, Yahaya Obiabo116, Ernest Nwazor117, Oluchi Ekenze118, Uduak Williams119, Alagoma Iyagba120, Lolade Taiwo121, Morenikeji Komolafe122, Konstantin Senkevich123, Chingiz Shashkin124, Nazira Zharkynbekova125, Kairgali Koneyev126, Ganieva Manizha127, Maksud Isrofilov127, Ulviyya Guliyeva128, Kamran Salayev129, Samson Khachatryan130, Salvatore Rossi131, Gabriella Silvestri131, Nourelhoda Haridy132, Luca A. Ramenghi133, Georgia Xiromerisiou134, Emanuele David135, Mhammed Aguennouz136, Liana Fidani137, Cleanthe Spanaki138, Arianna Tucci139, University College of London [London] (UCL), Instituto Giannina Gaslini, Genoa, University of Genoa (UNIGE), University of Washington [Seattle], Institute of Neurology, Queen Square, London, King‘s College London, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, Molecular and Clinical Sciences Institute - St George’s [London, UK] (Genetics Research Centre), University of London [London], Tel Aviv University Sackler School of Medicine [Tel Aviv, Israël], Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), GeneDx [Gaithersburg, MD, USA], Heidelberg University Hospital [Heidelberg], Royal Devon and Exeter NHS Foundation Trust [UK], Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Universita degli studi di Genova, Great Ormond Street Hospital for Children [London] (GOSH), The University of Sydney, Hofstra University [Hempstead], Università degli studi di Torino (UNITO), Hospital Sant Joan de Déu [Barcelona], Safra Children's Hospital, Seoul National University Hospital, Central South University [Changsha], Kennedy Krieger Institute [Baltimore], University of Amsterdam [Amsterdam] (UvA), University of Melbourne, Mayo Clinic [Rochester], Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, University of Ottawa [Ottawa], University of British Columbia (UBC), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Universidade de Santiago de Compostela [Spain] (USC ), Universiteit Leiden [Leiden], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Palermo - University of Palermo, University of Trieste, Universitat Autònoma de Barcelona (UAB), Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, University of California [Davis] (UC Davis), University of California-University of California, Children’s Hospital Colorado, University of Colorado Anschutz [Aurora], Washington University in Saint Louis (WUSTL), Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Department of Psychiatry, Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, University of Oxford [Oxford], University of São Paulo (USP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Service de Pédiatrie, CHUR Poitiers, Seoul National University [Seoul] (SNU), Pediatric Neurology and Neuromuscular Diseases Unit, University of Manchester [Manchester], Yale University School of Medicine, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Salvy-Córdoba, Nathalie, Università degli studi di Genova = University of Genoa (UniGe), Tel Aviv University (TAU), Università degli studi di Torino = University of Turin (UNITO), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Trieste = University of Trieste, University of California (UC)-University of California (UC), University of Oxford, Universidade de São Paulo = University of São Paulo (USP), Yale School of Medicine [New Haven, Connecticut] (YSM), Salpietro V, Dixon CL, Guo H, Bello OD, Vandrovcova J, Efthymiou S, Maroofian R, Heimer G, Burglen L, Valence S, Torti E, Hacke M, Rankin J, Tariq H, Colin E, Procaccio V, Striano P, Mankad K, Lieb A, Chen S, Pisani L, Bettencourt C, Männikkö R, Manole A, Brusco A, Grosso E, Ferrero GB, Armstrong-Moron J, Gueden S, Bar-Yosef O, Tzadok M, Monaghan KG, Santiago-Sim T, Person RE, Cho MT, Willaert R, Yoo Y, Chae JH, Quan Y, Wu H, Wang T, Bernier RA, Xia K, Blesson A, Jain M, Motazacker MM, Jaeger B, Schneider AL, Boysen K, Muir AM, Myers CT, Gavrilova RH, Gunderson L, Schultz-Rogers L, Klee EW, Dyment D, Osmond M, Parellada M, Llorente C, Gonzalez-Peñas J, Carracedo A, Van Haeringen A, Ruivenkamp C, Nava C, Heron D, Nardello R, Iacomino M, Minetti C, Skabar A, Fabretto A, SYNAPS Study Group, Raspall-Chaure M, Chez M, Tsai A, Fassi E, Shinawi M, Constantino JN, De Zorzi R, Fortuna S, Kok F, Keren B, Bonneau D, Choi M, Benzeev B, Zara F, Mefford HC, Scheffer IE, Clayton-Smith J, Macaya A, Rothman JE, Eichler EE, Kullmann DM, Houlden H, Salpietro, Vincenzo, Dixon, Christine L, Guo, Hui, Bello, Oscar D, Vandrovcova, Jana, Efthymiou, Stephanie, Maroofian, Reza, Heimer, Gali, Burglen, Lydie, Valence, Stephanie, Torti, Erin, Hacke, Moritz, Rankin, Julia, Tariq, Huma, Colin, Estelle, Procaccio, Vincent, Striano, Pasquale, Mankad, Kshitij, Lieb, Andrea, Chen, Sharon, Pisani, Laura, Bettencourt, Conceicao, Männikkö, Roope, Manole, Andreea, Brusco, Alfredo, Grosso, Enrico, Ferrero, Giovanni Battista, Armstrong-Moron, Judith, Gueden, Sophie, Bar-Yosef, Omer, Tzadok, Michal, Monaghan, Kristin G, Santiago-Sim, Teresa, Person, Richard E, Cho, Megan T, Willaert, Rebecca, Yoo, Yongjin, Chae, Jong-Hee, Quan, Yingting, Wu, Huidan, Wang, Tianyun, Bernier, Raphael A, Xia, Kun, Blesson, Alyssa, Jain, Mahim, Motazacker, Mohammad M, Jaeger, Bregje, Schneider, Amy L, Boysen, Katja, Muir, Alison M, Myers, Candace T, Gavrilova, Ralitza H, Gunderson, Lauren, Schultz-Rogers, Laura, Klee, Eric W, Dyment, David, Osmond, Matthew, Parellada, Mara, Llorente, Cloe, Gonzalez-Peñas, Javier, Carracedo, Angel, Van Haeringen, Arie, Ruivenkamp, Claudia, Nava, Caroline, Heron, Delphine, Nardello, Rosaria, Iacomino, Michele, Minetti, Carlo, Skabar, Aldo, Fabretto, Antonella, Raspall-Chaure, Miquel, Chez, Michael, Tsai, Anne, Fassi, Emily, Shinawi, Marwan, Constantino, John N, De Zorzi, Rita, Fortuna, Sara, Kok, Fernando, Keren, Bori, Bonneau, Dominique, Choi, Murim, Benzeev, Bruria, Zara, Federico, Mefford, Heather C, Scheffer, Ingrid E, Clayton-Smith, Jill, Macaya, Alfon, Rothman, James E, Eichler, Evan E, Kullmann, Dimitri M, Houlden, Henry, Salpietro1, Vincenzo, 3, 2, Dixon4, Christine L., Guo5, Hui, 140, 6, Bello Stephanie Efthymiou 1, Oscar D., Maroofian1, Reza, Heimer7, Gali, 8, Lydie Burglen, 9, Stephanie Valence, Torti 10, Erin, Hacke11, Moritz, Rankin12, Julia, Tariq1, Huma, Colin13, Estelle, Procaccio13, Vincent, Striano2, Pasquale, Mankad15, Kshitij, 4, Andreas Lieb, Chen16, Sharon, Pisani16, Laura, Bettencourt 17, Conceicao, 1, Roope Männikkö, Manole1, Andreea, Brusco 18, Alfredo, Grosso18, Enrico, Battista Ferrero19, Giovanni, Armstrong-Moron20, Judith, Gueden21, Sophie, Bar-Yosef7, Omer, Tzadok7, Michal, Monaghan10, Kristin G., Santiago-Sim10, Teresa, Person10, Richard E., Cho10, Megan T., Willaert10, Rebecca, Yoo22, Yongjin, Chae23, Jong-Hee, Quan6, Yingting, Wu6, Huidan, Wang5, Tianyun, Bernier24, Raphael A., Xia6, Kun, Blesson25, Alyssa, Jain25, Mahim, Motazacker26, Mohammad M., Jaeger27, Bregje, Schneider 28, Amy L., Boysen28, Katja, Muir 29, Alison M., Myers30, Candace T., Gavrilova31, Ralitza H., Gunderson31, Lauren, Schultz-Rogers 31, Laura, Klee31, Eric W., Dyment32, David, Osmond32, Matthew, 34, 33, Parellada35, Mara, Llorente36, Cloe, Gonzalez-Peñas37, Javier, Carracedo38, Angel, Van Haeringen40, Arie, Ruivenkamp40, Claudia, Nava41, Caroline, Heron41, Delphine, Nardello42, Rosaria, Iacomino43, Michele, Minetti2, Carlo, Skabar44, Aldo, Fabretto44, Antonella, Study GroupMiquel Raspall-Chaure45, Synap, Chez46, Michael, Tsai47, Anne, Fassi48, Emily, Shinawi48, Marwan, Constantino49, John N., De Zorzi50, Rita, Fortuna 50, Sara, Kok51, Fernando, Keren41, Bori, Bonneau13, Dominique, Choi 22, Murim, Benzeev7, Bruria, Zara43, Federico, Mefford29, Heather C., Scheffer28, Ingrid E., Clayton-Smith53, Jill, Macaya45, Alfon, Rothman4, James E., Eichler 5, Evan E., Kullmann 4 &amp, Dimitri M., 1, Henry Houlden, Hanna1, SYNAPS Study Group Michael G., Bugiardini1, Enrico, Hostettler1, Isabel, O’Callaghan1, Benjamin, Khan1, Alaa, Cortese1, Andrea, O’Connor1, Emer, Yau1, Wai Y., Bourinaris1, Thoma, Kaiyrzhanov1, Rauan, Chelban1, Viorica, Madej1, Monika, Diana2, Maria C., Vari2, Maria S., Pedemonte2, Marina, Bruno2, Claudio, Balagura3, Ganna, Scala3, Marcello, Fiorillo3, Chiara, Nobili3, Lino, Malintan4, Nancy T., Zanetti4, Maria N., Krishnakumar4, Shyam S., Lignani4, Gabriele, Jepson4, James E. C., Broda43, Paolo, Baldassari43, Simona, Rossi43, Pia, Fruscione43, Floriana, Madia43, Francesca, Traverso43, Monica, De-Marco43, Patrizia, Pérez-Dueñas45, Belen, Munell45, Francina, Kriouile57, Yamna, El-Khorassani57, Mohamed, Karashova58, Blagovesta, Avdjieva58, Daniela, Kathom58, Hadil, Tincheva58, Radka, Van-Maldergem59, Lionel, Nachbauer60, Wolfgang, Boesch60, Sylvia, Gagliano61, Antonella, Amadori62, Elisabetta, Goraya63, Jatinder S., Sultan64, Tipu, Kirmani65, Salman, Ibrahim66, Shahnaz, Jan66, Farida, Mine67, Jun, Banu68, Selina, Veggiotti69, Pierangelo, Zuccotti69, Gian V., Ferrari70, Michel D., Van Den Maagdenberg70, Arn M. J., Verrotti71, Alberto, Marseglia72, Gian L., Savasta72, Salvatore, Soler73, Miguel A., Scuderi74, Carmela, Borgione74, Eugenia, Chimenz75, Roberto, Gitto75, Eloisa, Dipasquale75, Valeria, Sallemi75, Alessia, Fusco75, Monica, Cuppari75, Caterina, Cutrupi75, Maria C., Ruggieri76, Martino, Cama77, Armando, Capra77, Valeria, Mencacci78, Niccolò E., Boles79, Richard, Gupta80, Neerja, Kabra80, Madhulika, Papacostas81, Savva, Zamba-Papanicolaou81, Eleni, Dardiotis82, Efthymio, Maqbool83, Shazia, Rana84, Nuzhat, Atawneh85, Osama, Lim86, Shen Y., Shaikh87, Farooq, Koutsis88, George, Breza88, Marianthi, Coviello89, Domenico A., Dauvilliers90, Yves A., Alkhawaja91, Issam, Alkhawaja92, Mariam, Al-Mutairi93, Fuad, Stojkovic94, Tanya, Ferrucci, Veronica, Zollo, Massimo, Alkuraya96, Fowzan S., Kinali97, Maria, Sherifa98, Hamed, Benrhouma99, Hanene, Turki99, Ilhem B. Y., Tazir100, Meriem, Obeid101, Makram, Bakhtadze102, Sophia, Saadi103, Nebal W., Zaki104, Maha S., Triki105, Chahnez C., Benfenati106, Fabio, Gustincich106, Stefano, Kara107, Majdi, Belcastro108, Vincenzo, Specchio109, Nicola, Capovilla110, Giuseppe, Karimiani111, Ehsan G., Salih112, Ahmed M., Okubadejo113, Njideka U., Ojo113, Oluwadamilola O., Oshinaike113, Olajumoke O., Oguntunde113, Olapeju, Wahab114, Kolawole, Bello114, Abiodun H., Abubakar115, Sanni, Obiabo116, Yahaya, Nwazor117, Ernest, Ekenze118, Oluchi, Williams119, Uduak, Iyagba120, Alagoma, Taiwo121, Lolade, Komolafe122, Morenikeji, Senkevich123, Konstantin, Shashkin124, Chingiz, Zharkynbekova125, Nazira, Koneyev126, Kairgali, Manizha127, Ganieva, Isrofilov127, Maksud, Guliyeva128, Ulviyya, Salayev129, Kamran, Khachatryan130, Samson, Rossi131, Salvatore, Silvestri131, Gabriella, Haridy132, Nourelhoda, Ramenghi133, Luca A., Xiromerisiou134, Georgia, David135, Emanuele, Aguennouz136, Mhammed, Fidani137, Liana, Spanaki138 &amp, Cleanthe, and Tucci139, Arianna

Subjects
Male, [SDV.GEN] Life Sciences [q-bio]/Genetics, Ion channels in the nervous system, Cohort Studies, fluids and secretions, Loss of Function Mutation, Receptors, AMPA, AMPA receptor, lcsh:Science, Child, reproductive and urinary physiology, AMPA receptor, GluA2, neurodevelopmental disorders, autism spectrum disorder, glutamatergic synaptic transmission, GRIA2, neurodevelopmental disorders, Developmental disorders, Neurodevelopmental disorders, Brain, Magnetic Resonance Imaging, Settore MED/26 - NEUROLOGIA, GluA2, Child, Preschool, Female, Adult, Heterozygote, Adolescent, Science, autism spectrum disorder, Article, Young Adult, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Intellectual Disability/genetics, Neurodevelopmental Disorders/genetics, Receptors AMPA/genetics, Intellectual Disability, mental disorders, Humans, Infant, Neurodevelopmental Disorders, Receptors, AMPA, GRIA2, Preschool, Ion channel in the nervous system, Developmental disorders, Synaptic development, NG sequencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, glutamatergic synaptic transmission, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, NG sequencing, Synaptic development, Ion channel in the nervous system, Next-generation sequencing, lcsh:Q
Abstract

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission., Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca2+ transport and AMPAR currents.”

Published
2019

21. SAHA (Vorinostat) Corrects Inhibitory Synaptic Deficits Caused by Missense Epilepsy Mutations to the GABA A Receptor γ2 Subunit.

Author

Durisic N, Keramidas A, Dixon CL, and Lynch JW

Abstract

The GABA A receptor (GABA A R) α1 subunit A295D epilepsy mutation reduces the surface expression of α1 A295D β2γ2 GABA A Rs via ER-associated protein degradation. Suberanilohydroxamic acid (SAHA, also known as Vorinostat) was recently shown to correct the misfolding of α1 A295D subunits and thereby enhance the functional surface expression of α1 A295D β2γ2 GABA A Rs. Here we investigated whether SAHA can also restore the surface expression of γ2 GABA A R subunits that incorporate epilepsy mutations (N40S, R43Q, P44S, R138G) known to reduce surface expression via ER-associated protein degradation. As a control, we also investigated the γ2 K289M epilepsy mutation that impairs gating without reducing surface expression. Effects of mutations were evaluated on inhibitory postsynaptic currents (IPSCs) mediated by the major synaptic α1β2γ2 GABA A R isoform. Recordings were performed in neuron-HEK293 cell artificial synapses to minimise contamination by GABA A Rs of undefined subunit composition. Transfection with α1β2γ2 N40S , α1β2γ2 R43Q , α1β2γ2 P44S and α1β2γ2 R138G subunits produced IPSCs with decay times slower than those of unmutated α1β2γ2 GABA A Rs due to the low expression of mutant γ2 subunits and the correspondingly high expression of slow-decaying α1β2 GABA A Rs. SAHA pre-treatment significantly accelerated the decay time constants of IPSCs consistent with the upregulation of mutant γ2 subunit expression. This increase in surface expression was confirmed by immunohistochemistry. SAHA had no effect on either the IPSC kinetics or surface expression levels of α1β2γ2 K289M GABA A Rs, confirming its specificity for ER-retained mutant γ2 subunits. We also found that α1β2γ2 K289M GABA A Rs and SAHA-treated α1β2γ2 R43Q , α1β2γ2 P44S and α1β2γ2 R138G GABA A Rs all mediated IPSCs that decayed at significantly faster rates than wild type receptors as temperature was increased from 22 to 40°C. This may help explain why these mutations cause febrile seizures (FS). Given that SAHA is approved by therapeutic regulatory agencies for human use, we propose that it may be worth investigating as a treatment for epilepsies caused by the N40S, R43Q, P44S and R138G mutations. Although SAHA has already been proposed as a therapeutic for patients harbouring the α1 A295D epilepsy mutation, the present study extends its potential utility to a new subunit and four new mutations.

Published
2018
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