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.
AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders / Salpietro1, Vincenzo; 3, 2; 140, ; Dixon4, Christine L.; 140, ; Guo5, Hui; 140, 6; Bello Stephanie Efthymiou 1, Oscar D.; 4, ; Maroofian1, Reza; Heimer7, Gali; 8, Lydie Burglen; 9, Stephanie Valence; Torti 10, Erin; Hacke11, Moritz; Rankin12, Julia; Tariq1, Huma; Colin13, Estelle; 14, ; Procaccio13, Vincent; 14, ; Striano2, Pasquale; 3, ; 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; 6, ; 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; 39, ; Van Haeringen40, Arie; Ruivenkamp40, Claudia; Nava41, Caroline; Heron41, Delphine; Nardello42, Rosaria; Iacomino43, Michele; Minetti2, Carlo; 3, ; Skabar44, Aldo; Fabretto44, Antonella; Study GroupMiquel Raspall-Chaure45, Synaps; Chez46, Michael; Tsai47, Anne; Fassi48, Emily; Shinawi48, Marwan; Constantino49, John N.; De Zorzi50, Rita; Fortuna 50, Sara; Kok51, Fernando; 52, ; Keren41, Boris; Bonneau13, Dominique; 14, ; Choi 22, Murim; Benzeev7, Bruria; Zara43, Federico; Mefford29, Heather C.; Scheffer28, Ingrid E.; Clayton-Smith53, Jill; 54, ; Macaya45, Alfons; Rothman4, James E.; 55, ; Eichler 5, Evan E.; 56, ; Kullmann 4 &, 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, Thomas; 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, Savvas; Zamba-Papanicolaou81, Eleni; Dardiotis82, Efthymios; 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 &, Cleanthe; Tucci139, Arianna. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:1(2019), p. 3094. [10.1038/s41467-019-10910-w]
AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders
Veronica FerrucciMembro del Collaboration Group
;Massimo ZolloMembro del Collaboration Group
;
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.| File | Dimensione | Formato | |
|---|---|---|---|
|
SALPIETRO ET AL 2019.pdf
accesso aperto
Tipologia:
Documento in Post-print
Licenza:
Dominio pubblico
Dimensione
2.62 MB
Formato
Adobe PDF
|
2.62 MB | Adobe PDF | Visualizza/Apri |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
