AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

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.; Chen, S.; Pisani, L.; Bettencourt, C.; Mannikko, R.; Manole, A.; Brusco, A.; Grosso, E.; Ferrero, G.B.; Armstrong-Moron, J.; Gueden, S.; Bar-Yosef, O.; Tzadok, M.; Monaghan, K.G.; Santiago-Sim, T.; Person, R.E.; Cho, M.T.; Willaert, R.; Yoo, Y.; Chae, J.-.; Quan, Y.; Wu, H.; Wang, T.; Bernier, R.A.; Xia, K.; Blesson, A.; Jain, M.; Motazacker, M.M.; Jaeger, B.; Schneider, A.L.; Boysen, K.; Muir, A.M.; Myers, C.T.; Gavrilova, R.H.; Gunderson, L.; Schultz-Rogers, L.; Klee, E.W.; Dyment, D.; Osmond, M.; Parellada, M.; Llorente, C.; Gonzalez-Penas, J.; Carracedo, A.; Van Haeringen, A.; Ruivenkamp, C.; Nava, C.; Heron, D.; Nardello, R.; Iacomino, M.; Minetti, C.; Skabar, A.; Fabretto, A.; Hanna, M.G.; Bugiardini, E.; Hostettler, I.; O'Callaghan, B.; Khan, A.; Cortese, A.; O'Connor, E.; Yau, W.Y.; Bourinaris, T.; Kaiyrzhanov, R.; Chelban, V.; Madej, M.; Diana, M.C.; Vari, M.S.; Pedemonte, M.; Bruno, C.; Balagura, G.; Scala, M.; Fiorillo, C.; Nobili, L.; Malintan, N.T.; Zanetti, M.N.; Krishnakumar, S.S.; Lignani, G.; Jepson, J.E.C.; Broda, P.; Baldassari, S.; Rossi, P.; Fruscione, F.; Madia, F.; Traverso, M.; De-Marco, P.; Perez-Duenas, 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, J.S.; Sultan, T.; Kirmani, S.; Ibrahim, S.; Jan, F.; Mine, J.; Banu, S.; Veggiotti, P.; Zuccotti, G.V.; Ferrari, M.D.; Van Den Maagdenberg, A.M.J.; Verrotti, A.; Marseglia, G.L.; Savasta, S.; Soler, M.A.; Scuderi, C.; Borgione, E.; Chimenz, R.; Gitto, E.; Dipasquale, V.; Sallemi, A.; Fusco, M.; Cuppari, C.; Cutrupi, M.C.; Ruggieri, M.; Cama, A.; Capra, V.; Mencacci, N.E.; Boles, R.; Gupta, N.; Kabra, M.; Papacostas, S.; Zamba-Papanicolaou, E.; Dardiotis, E.; Maqbool, S.; Rana, N.; Atawneh, O.; Lim, S.Y.; Shaikh, F.; Koutsis, G.; Breza, M.; Coviello, D.A.; Dauvilliers, Y.A.; Alkhawaja, I.; Alkhawaja, M.; Al-Mutairi, F.; Stojkovic, T.; Ferrucci, V.; Zollo, M.; Alkuraya, F.S.; Kinali, M.; Sherifa, H.; Benrhouma, H.; Turki, I.B.Y.; Tazir, M.; Obeid, M.; Bakhtadze, S.; Saadi, N.W.; Zaki, M.S.; Triki, C.C.; Benfenati, F.; Gustincich, S.; Kara, M.; Belcastro, V.; Specchio, N.; Capovilla, G.; Karimiani, E.G.; Salih, A.M.; Okubadejo, N.U.; Ojo, O.O.; Oshinaike, O.O.; Oguntunde, O.; Wahab, K.; Bello, A.H.; 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, L.A.; Xiromerisiou, G.; David, E.; Aguennouz, M.; Fidani, L.; Spanaki, C.; Tucci, A.; Raspall-Chaure, M.; Chez, M.; Tsai, A.; Fassi, E.; Shinawi, M.; Constantino, J.N.; De Zorzi, R.; Fortuna, S.; Kok, F.; Keren, B.; Bonneau, D.; Choi, M.; Benzeev, B.; Zara, F.; Mefford, H.C.; Scheffer, I.E.; Clayton-Smith, J.; Macaya, A.; Rothman, J.E.; Eichler, E.E.; Kullmann, D.M.; Houlden, H.

doi:10.1038/s41467-019-10910-w

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. (SYNAPS Study Grp)

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders / V. Salpietro, C.L. Dixon, H. Guo, O.D. Bello, J. Vandrovcova, S. Efthymiou, R. Maroofian, G. Heimer, L. Burglen, S. Valence, E. Torti, M. Hacke, J. Rankin, H. Tariq, E. Colin, V. Procaccio, P. Striano, K. Mankad, A. Lieb, S. Chen, L. Pisani, C. Bettencourt, R. Mannikko, A. Manole, A. Brusco, E. Grosso, G.B. Ferrero, J. Armstrong-Moron, S. Gueden, O. Bar-Yosef, M. Tzadok, K.G. Monaghan, T. Santiago-Sim, R.E. Person, M.T. Cho, R. Willaert, Y. Yoo, J.-. Chae, Y. Quan, H. Wu, T. Wang, R.A. Bernier, K. Xia, A. Blesson, M. Jain, M.M. Motazacker, B. Jaeger, A.L. Schneider, K. Boysen, A.M. Muir, C.T. Myers, R.H. Gavrilova, L. Gunderson, L. Schultz-Rogers, E.W. Klee, D. Dyment, M. Osmond, M. Parellada, C. Llorente, J. Gonzalez-Penas, A. Carracedo, A. Van Haeringen, C. Ruivenkamp, C. Nava, D. Heron, R. Nardello, M. Iacomino, C. Minetti, A. Skabar, A. Fabretto, M.G. Hanna, E. Bugiardini, I. Hostettler, B. O'Callaghan, A. Khan, A. Cortese, E. O'Connor, W.Y. Yau, T. Bourinaris, R. Kaiyrzhanov, V. Chelban, M. Madej, M.C. Diana, M.S. Vari, M. Pedemonte, C. Bruno, G. Balagura, M. Scala, C. Fiorillo, L. Nobili, N.T. Malintan, M.N. Zanetti, S.S. Krishnakumar, G. Lignani, J.E.C. Jepson, P. Broda, S. Baldassari, P. Rossi, F. Fruscione, F. Madia, M. Traverso, P. De-Marco, B. Perez-Duenas, F. Munell, Y. Kriouile, M. El-Khorassani, B. Karashova, D. Avdjieva, H. Kathom, R. Tincheva, L. Van-Maldergem, W. Nachbauer, S. Boesch, A. Gagliano, E. Amadori, J.S. Goraya, T. Sultan, S. Kirmani, S. Ibrahim, F. Jan, J. Mine, S. Banu, P. Veggiotti, G.V. Zuccotti, M.D. Ferrari, A.M.J. Van Den Maagdenberg, A. Verrotti, G.L. Marseglia, S. Savasta, M.A. Soler, C. Scuderi, E. Borgione, R. Chimenz, E. Gitto, V. Dipasquale, A. Sallemi, M. Fusco, C. Cuppari, M.C. Cutrupi, M. Ruggieri, A. Cama, V. Capra, N.E. Mencacci, R. Boles, N. Gupta, M. Kabra, S. Papacostas, E. Zamba-Papanicolaou, E. Dardiotis, S. Maqbool, N. Rana, O. Atawneh, S.Y. Lim, F. Shaikh, G. Koutsis, M. Breza, D.A. Coviello, Y.A. Dauvilliers, I. Alkhawaja, M. Alkhawaja, F. Al-Mutairi, T. Stojkovic, V. Ferrucci, M. Zollo, F.S. Alkuraya, M. Kinali, H. Sherifa, H. Benrhouma, I.B.Y. Turki, M. Tazir, M. Obeid, S. Bakhtadze, N.W. Saadi, M.S. Zaki, C.C. Triki, F. Benfenati, S. Gustincich, M. Kara, V. Belcastro, N. Specchio, G. Capovilla, E.G. Karimiani, A.M. Salih, N.U. Okubadejo, O.O. Ojo, O.O. Oshinaike, O. Oguntunde, K. Wahab, A.H. Bello, S. Abubakar, Y. Obiabo, E. Nwazor, O. Ekenze, U. Williams, A. Iyagba, L. Taiwo, M. Komolafe, K. Senkevich, C. Shashkin, N. Zharkynbekova, K. Koneyev, G. Manizha, M. Isrofilov, U. Guliyeva, K. Salayev, S. Khachatryan, S. Rossi, G. Silvestri, N. Haridy, L.A. Ramenghi, G. Xiromerisiou, E. David, M. Aguennouz, L. Fidani, C. Spanaki, A. Tucci, M. Raspall-Chaure, M. Chez, A. Tsai, E. Fassi, M. Shinawi, J.N. Constantino, R. De Zorzi, S. Fortuna, F. Kok, B. Keren, D. Bonneau, M. Choi, B. Benzeev, F. Zara, H.C. Mefford, I.E. Scheffer, J. Clayton-Smith, A. Macaya, J.E. Rothman, E.E. Eichler, D.M. Kullmann, H. Houlden. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:1(2019 Jul 12), pp. 3094.1-3094.16. [10.1038/s41467-019-10910-w]

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Salpietro V.^Primo;Dixon C. L.^Secondo;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.;Chen S.;Pisani L.;Bettencourt C.;Mannikko R.;Manole A.;Brusco A.;Grosso E.;Ferrero G. B.;Armstrong-Moron J.;Gueden S.;Bar-Yosef O.;Tzadok M.;Monaghan K. G.;Santiago-Sim T.;Person R. E.;Cho M. T.;Willaert R.;Yoo Y.;Chae J. -H.;Quan Y.;Wu H.;Wang T.;Bernier R. A.;Xia K.;Blesson A.;Jain M.;Motazacker M. M.;Jaeger B.;Schneider A. L.;Boysen K.;Muir A. M.;Myers C. T.;Gavrilova R. H.;Gunderson L.;Schultz-Rogers L.;Klee E. W.;Dyment D.;Osmond M.;Parellada M.;Llorente C.;Gonzalez-Penas J.;Carracedo A.;Van Haeringen A.;Ruivenkamp C.;Nava C.;Heron D.;Nardello R.;Iacomino M.;Minetti C.;Skabar A.;Fabretto A.;Hanna M. G.;Bugiardini E.;Hostettler I.;O'Callaghan B.;Khan A.;A. Cortese;O'Connor E.;Yau W. Y.;Bourinaris T.;Kaiyrzhanov R.;Chelban V.;Madej M.;Diana M. C.;Vari M. S.;Pedemonte M.;Bruno C.;Balagura G.;Scala M.;Fiorillo C.;Nobili L.;Malintan N. T.;Zanetti M. N.;Krishnakumar S. S.;Lignani G.;Jepson J. E. C.;Broda P.;Baldassari S.;Rossi P.;Fruscione F.;Madia F.;Traverso M.;De-Marco P.;Perez-Duenas 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 J. S.;Sultan T.;Kirmani S.;Ibrahim S.;Jan F.;Mine J.;Banu S.;P. Veggiotti;G.V. Zuccotti;Ferrari M. D.;Van Den Maagdenberg A. M. J.;Verrotti A.;Marseglia G. L.;Savasta S.;Soler M. A.;Scuderi C.;Borgione E.;Chimenz R.;Gitto E.;Dipasquale V.;Sallemi A.;Fusco M.;Cuppari C.;Cutrupi M. C.;Ruggieri M.;Cama A.;Capra V.;Mencacci N. E.;Boles R.;Gupta N.;Kabra M.;Papacostas S.;Zamba-Papanicolaou E.;Dardiotis E.;Maqbool S.;Rana N.;Atawneh O.;Lim S. Y.;Shaikh F.;Koutsis G.;Breza M.;Coviello D. A.;Dauvilliers Y. A.;AlKhawaja I.;AlKhawaja M.;Al-Mutairi F.;Stojkovic T.;Ferrucci V.;Zollo M.;Alkuraya F. S.;Kinali M.;Sherifa H.;Benrhouma H.;Turki I. B. Y.;Tazir M.;Obeid M.;Bakhtadze S.;Saadi N. W.;Zaki M. S.;Triki C. C.;Benfenati F.;Gustincich S.;Kara M.;Belcastro V.;Specchio N.;Capovilla G.;Karimiani E. G.;Salih A. M.;Okubadejo N. U.;Ojo O. O.;Oshinaike O. O.;Oguntunde O.;Wahab K.;Bello A. H.;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 L. A.;Xiromerisiou G.;David E.;Aguennouz M.;Fidani L.;Spanaki C.^Penultimo;Tucci A.^Ultimo;Raspall-Chaure M.;Chez M.;Tsai A.;Fassi E.;Shinawi M.;Constantino J. N.;De Zorzi R.;Fortuna S.;Kok F.;Keren B.;Bonneau D.;Choi M.;Benzeev B.;Zara F.;Mefford H. C.;Scheffer I. E.;Clayton-Smith J.;Macaya A.;Rothman J. E.;Eichler E. E.;Kullmann D. M.;Houlden H.

2019

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. (SYNAPS Study Grp)

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	Settori scientifico-disciplinari dell'articolo (validi dal 09/05/2024)
	
				Settore MEDS-01/A - Genetica medica
Settore MEDS-12/A - Neurologia
			
	Titolo del progetto
	
	Titolo Progetto
	
									Integrated European omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases
								
	Acronimo
	
									NEUROMICS
								
	Nome finanziatore
	
										EUROPEAN COMMISSION
									
	Finanziamento
	
									FP7
								
	N. Contratto
	
									305121
								
	Data di pubblicazione
	
				12-lug-2019
			
	Rivista in ANCE
	
				NATURE COMMUNICATIONS
			
	DOI
	
				https://dx.doi.org/10.1038/s41467-019-10910-w
			
	URL
	
				http://www.nature.com/ncomms/index.html
			
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				Article (author)
			
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				01 - Articolo su periodico

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