AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

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

doi:10.1038/s41467-019-10910-w

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

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

Risultato della ricerca: Contributo in rivista › Articolo in rivista

34 Citazioni (Scopus)

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.

Lingua originale	English
pagine (da-a)	3094-N/A
Rivista	Nature Communications
Volume	10
DOI	https://doi.org/10.1038/s41467-019-10910-w
Stato di pubblicazione	Pubblicato - 2019

Keywords

AMPA receptor
Adolescent
Adult
Brain
Child
Child, Preschool
Cohort Studies
Female
Heterozygote
Humans
Infant
Intellectual Disability
Loss of Function Mutation
Magnetic Resonance Imaging
Male
Neurodevelopmental Disorders
Receptors, AMPA
Young Adult

Accesso al documento

10.1038/s41467-019-10910-w

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Open Access link a IRIS PubliCatt

Cita questo

Salpietro, V., Dixon, C. L., Guo, H., Bello, O. D., 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., ... Houlden, H. (2019). AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders. Nature Communications, 10, 3094-N/A. https://doi.org/10.1038/s41467-019-10910-w

@article{c3c8f9e5087548dfb01fa4023264e38e,

title = "AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders",

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.",

keywords = "AMPA receptor, Adolescent, Adult, Brain, Child, Child, Preschool, Cohort Studies, Female, Heterozygote, Humans, Infant, Intellectual Disability, Loss of Function Mutation, Magnetic Resonance Imaging, Male, Neurodevelopmental Disorders, Receptors, AMPA, Young Adult, AMPA receptor, Adolescent, Adult, Brain, Child, Child, Preschool, Cohort Studies, Female, Heterozygote, Humans, Infant, Intellectual Disability, Loss of Function Mutation, Magnetic Resonance Imaging, Male, Neurodevelopmental Disorders, Receptors, AMPA, Young Adult",

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

year = "2019",

doi = "10.1038/s41467-019-10910-w",

language = "English",

volume = "10",

pages = "3094--N/A",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

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, J-H, 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, Hanna, MG, Bugiardini, E, Hostettler, I, O’Callaghan, B, Khan, A, Cortese, A, O’Connor, E, Yau, WY, Bourinaris, T, Kaiyrzhanov, R, Chelban, V, Madej, M, Diana, MC, Vari, MS, Pedemonte, M, Bruno, C, Balagura, G, Scala, M, Fiorillo, C, Nobili, L, Malintan, NT, Zanetti, MN, Krishnakumar, SS, Lignani, G, Jepson, JEC, Broda, P, Baldassari, S, Rossi, P, Fruscione, F, Madia, F, Traverso, M, De-Marco, P, Pérez-Dueñas, B, Munell, F, Kriouile, Y, El-Khorassani, M, Karashova, B, Avdjieva, D, Kathom, H, Tincheva, R, Van-Maldergem, L, Nachbauer, W, Boesch, S, Gagliano, A, Amadori, E, Goraya, JS, Sultan, T, Kirmani, S, Ibrahim, S, Jan, F, Mine, J, Banu, S, Veggiotti, P, Zuccotti, GV, Ferrari, MD, Van Den Maagdenberg, AMJ, Verrotti, A, Marseglia, GL, Savasta, S, Soler, MA, Scuderi, C, Borgione, E, Chimenz, R, Gitto, E, Dipasquale, V, Sallemi, A, Fusco, M, Cuppari, C, Cutrupi, MC, Ruggieri, M, Cama, A, Capra, V, Mencacci, NE, Boles, R, Gupta, N, Kabra, M, Papacostas, S, Zamba-Papanicolaou, E, Dardiotis, E, Maqbool, S, Rana, N, Atawneh, O, Lim, SY, Shaikh, F, Koutsis, G, Breza, M, Coviello, DA, Dauvilliers, YA, Alkhawaja, I, Alkhawaja, M, Al-Mutairi, F, Stojkovic, T, Ferrucci, V, Zollo, M, Alkuraya, FS, Kinali, M, Sherifa, H, Benrhouma, H, Turki, IBY, Tazir, M, Obeid, M, Bakhtadze, S, Saadi, NW, Zaki, MS, Triki, CC, Benfenati, F, Gustincich, S, Kara, M, Belcastro, V, Specchio, N, Capovilla, G, Karimiani, EG, Salih, AM, Okubadejo, NU, Ojo, OO, Oshinaike, OO, Oguntunde, O, Wahab, K, Bello, AH, Abubakar, S, Obiabo, Y, Nwazor, E, Ekenze, O, Williams, U, Iyagba, A, Taiwo, L, Komolafe, M, Senkevich, K, Shashkin, C, Zharkynbekova, N, Koneyev, K, Manizha, G, Isrofilov, M, Guliyeva, U, Salayev, K, Khachatryan, S, Rossi, S , Silvestri, G, Haridy, N, Ramenghi, LA, Xiromerisiou, G, David, E, Aguennouz, M, Fidani, L, Spanaki, C, Tucci, A, 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 2019, 'AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders', Nature Communications, vol. 10, pagg. 3094-N/A. https://doi.org/10.1038/s41467-019-10910-w

TY - JOUR

T1 - AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

AU - Salpietro, Vincenzo

AU - Dixon, Christine L.

AU - Guo, Hui

AU - Bello, Oscar D.

AU - Vandrovcova, Jana

AU - Efthymiou, Stephanie

AU - Maroofian, Reza

AU - Heimer, Gali

AU - Burglen, Lydie

AU - Valence, Stephanie

AU - Torti, Erin

AU - Hacke, Moritz

AU - Rankin, Julia

AU - Tariq, Huma

AU - Colin, Estelle

AU - Procaccio, Vincent

AU - Striano, Pasquale

AU - Mankad, Kshitij

AU - Lieb, Andreas

AU - Chen, Sharon

AU - Pisani, Laura

AU - Bettencourt, Conceicao

AU - Männikkö, Roope

AU - Manole, Andreea

AU - Brusco, Alfredo

AU - Grosso, Enrico

AU - Ferrero, Giovanni Battista

AU - Armstrong-Moron, Judith

AU - Gueden, Sophie

AU - Bar-Yosef, Omer

AU - Tzadok, Michal

AU - Monaghan, Kristin G.

AU - Santiago-Sim, Teresa

AU - Person, Richard E.

AU - Cho, Megan T.

AU - Willaert, Rebecca

AU - Yoo, Yongjin

AU - Chae, Jong-Hee

AU - Quan, Yingting

AU - Wu, Huidan

AU - Wang, Tianyun

AU - Bernier, Raphael A.

AU - Xia, Kun

AU - Blesson, Alyssa

AU - Jain, Mahim

AU - Motazacker, Mohammad M.

AU - Jaeger, Bregje

AU - Schneider, Amy L.

AU - Boysen, Katja

AU - Muir, Alison M.

AU - Myers, Candace T.

AU - Gavrilova, Ralitza H.

AU - Gunderson, Lauren

AU - Schultz-Rogers, Laura

AU - Klee, Eric W.

AU - Dyment, David

AU - Osmond, Matthew

AU - Parellada, Mara

AU - Llorente, Cloe

AU - Gonzalez-Peñas, Javier

AU - Carracedo, Angel

AU - Van Haeringen, Arie

AU - Ruivenkamp, Claudia

AU - Nava, Caroline

AU - Heron, Delphine

AU - Nardello, Rosaria

AU - Iacomino, Michele

AU - Minetti, Carlo

AU - Skabar, Aldo

AU - Fabretto, Antonella

AU - Hanna, Michael G.

AU - Bugiardini, Enrico

AU - Hostettler, Isabel

AU - O’Callaghan, Benjamin

AU - Khan, Alaa

AU - Cortese, Andrea

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AU - Rossi, Salvatore

AU - Silvestri, Gabriella

AU - Haridy, Nourelhoda

AU - Ramenghi, Luca A.

AU - Xiromerisiou, Georgia

AU - David, Emanuele

AU - Aguennouz, Mhammed

AU - Fidani, Liana

AU - Spanaki, Cleanthe

AU - Tucci, Arianna

AU - Raspall-Chaure, Miquel

AU - Chez, Michael

AU - Tsai, Anne

AU - Fassi, Emily

AU - Shinawi, Marwan

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AU - Fortuna, Sara

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AU - Bonneau, Dominique

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AU - Zara, Federico

AU - Mefford, Heather C.

AU - Scheffer, Ingrid E.

AU - Clayton-Smith, Jill

AU - Macaya, Alfons

AU - Rothman, James E.

AU - Eichler, Evan E.

AU - Kullmann, Dimitri M.

AU - Houlden, Henry

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - AMPA receptor

KW - Adolescent

KW - Adult

KW - Brain

KW - Child

KW - Child, Preschool

KW - Cohort Studies

KW - Female

KW - Heterozygote

KW - Humans

KW - Infant

KW - Intellectual Disability

KW - Loss of Function Mutation

KW - Magnetic Resonance Imaging

KW - Male

KW - Neurodevelopmental Disorders

KW - Receptors, AMPA

KW - Young Adult

KW - AMPA receptor

KW - Adolescent

KW - Adult

KW - Brain

KW - Child

KW - Child, Preschool

KW - Cohort Studies

KW - Female

KW - Heterozygote

KW - Humans

KW - Infant

KW - Intellectual Disability

KW - Loss of Function Mutation

KW - Magnetic Resonance Imaging

KW - Male

KW - Neurodevelopmental Disorders

KW - Receptors, AMPA

KW - Young Adult

UR - http://hdl.handle.net/10807/170970

U2 - 10.1038/s41467-019-10910-w

DO - 10.1038/s41467-019-10910-w

M3 - Article

SN - 2041-1723

VL - 10

SP - 3094-N/A

JO - Nature Communications

JF - Nature Communications

ER -

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

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