AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders
Vincenzo Salpietro
(1, 2, 3)
,
Christine Dixon
(1)
,
Hui Guo
(4)
,
Oscar Bello
(5)
,
Jana J Vandrovcova
(6)
,
Stephanie Efthymiou
(7)
,
Reza Maroofian
(8)
,
Gali Heimer
(9)
,
Lydie Burglen
(10)
,
Stephanie Valence
(10)
,
Erin Torti
(11)
,
Moritz Hacke
(12)
,
Julia Rankin
(13)
,
Huma Tariq
(1)
,
Estelle Colin
(14, 15)
,
Vincent Procaccio
(14, 15)
,
Pasquale Striano
(3)
,
Kshitij Mankad
(16)
,
Andreas Lieb
(1)
,
Sharon Chen
(17)
,
Laura Pisani
(18)
,
Conceição Bettencourt
(1)
,
Roope Männikkö
(1)
,
Andreea Manole
(1)
,
Alfredo Brusco
(19)
,
Enrico Del Grosso
(19)
,
Giovanni Battista Ferrero
(19)
,
Judith Armstrong-Moron
(20)
,
Sophie Gueden
(15)
,
Omer Bar-Yosef
(21)
,
Michal Tzadok
(21)
,
Kristin Monaghan
(11)
,
Teresa Santiago-Sim
(11)
,
Richard E. Person
(11)
,
Megan T Cho
(11)
,
Rebecca Willaert
(11)
,
Yongjin Yoo
(22)
,
Jong-Hee Chae
(22)
,
Yingting Quan
(23)
,
Huidan Wu
(23)
,
Tianyun Wang
(23)
,
Raphael Bernier
(4)
,
Kun Xia
(23)
,
Alyssa Blesson
(24)
,
Mahim Jain
(24)
,
Mohammad Motazacker
(25)
,
Bregje Jaeger
(25)
,
Amy Schneider
(26)
,
Katja Boysen
(26)
,
Alison Muir
(4)
,
Candace Myers
(4)
,
Ralitza Gavrilova
(27)
,
Lauren Gunderson
(27)
,
Laura Schultz-Rogers
(27)
,
Eric Klee
(28)
,
David Dyment
(29)
,
Matthew M Osmond
(30)
,
Mara Parellada
(31)
,
Cloe Llorente
(31)
,
Javier Gonzalez-Peñas
(31)
,
Angel Carracedo
(32)
,
Arie van Haeringen
(33)
,
Claudia Ruivenkamp
(33)
,
Caroline Nava
(34)
,
Delphine Héron
(35)
,
Rosaria Nardello
(36)
,
Michele Iacomino
(3)
,
Carlo Minetti
(3)
,
Aldo Skabar
(37)
,
Antonella Fabretto
(37)
,
Miquel Raspall-Chaure
(38)
,
Michael Chez
(39)
,
Anne Tsai
(40)
,
Emily Fassi
(41)
,
Marwan Shinawi
(42)
,
John N. Constantino
(43)
,
Rita de Zorzi
(44)
,
Sara Fortuna
(37)
,
Fernando Kok
(45)
,
Boris Keren
(35)
,
Dominique Bonneau
(46)
,
Murim Choi
(47)
,
Bruria Benzeev
(21)
,
Federico Zara
(48)
,
Heather Mefford
(4)
,
Ingrid E. Scheffer
(26)
,
Jill Clayton-Smith
(49)
,
Alfons Macaya
(38)
,
James E Rothman
(50)
,
Evan Eichler
(4)
,
Dimitri Kullmann
(1)
,
Henry Houlden
(1)
,
Yves Dauvilliers
(51)
1
UCL -
University College of London [London]
2 Instituto Giannina Gaslini, Genoa
3 UniGe - Università degli studi di Genova = University of Genoa
4 University of Washington [Seattle]
5 Institute of Neurology, Queen Square, London
6 King‘s College London
7 UCL Institute of Neurology, Queen Square [London]
8 Genetics Research Centre - Molecular and Clinical Sciences Institute - St George’s [London, UK]
9 TAU - Tel Aviv University
10 CHU Trousseau [APHP]
11 GeneDx [Gaithersburg, MD, USA]
12 Heidelberg University Hospital [Heidelberg]
13 Royal Devon and Exeter NHS Foundation Trust [UK]
14 BNMI - Biologie Neurovasculaire et Mitochondriale Intégrée
15 CHU Angers - Centre Hospitalier Universitaire d'Angers
16 GOSH - Great Ormond Street Hospital for Children [London]
17 The University of Sydney
18 Hofstra University [Hempstead]
19 UNITO - Università degli studi di Torino = University of Turin
20 Hospital Sant Joan de Déu [Barcelona]
21 Safra Children's Hospital
22 Seoul National University Hospital
23 Central South University [Changsha]
24 Kennedy Krieger Institute [Baltimore]
25 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
26 University of Melbourne
27 Mayo Clinic [Rochester]
28 HSR - Department of Health Sciences Research [Mayo Clinic]
29 University of Ottawa [Ottawa]
30 UBC - University of British Columbia
31 UCM - Universidad Complutense de Madrid = Complutense University of Madrid [Madrid]
32 USC - Universidade de Santiago de Compostela [Spain]
33 Universiteit Leiden = Leiden University
34 ICM - Institut du Cerveau = Paris Brain Institute
35 CHU Pitié-Salpêtrière [AP-HP]
36 Università degli studi di Palermo - University of Palermo
37 Università degli studi di Trieste = University of Trieste
38 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
39 Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento
40 Children’s Hospital Colorado
41 WUSTL - Washington University in Saint Louis
42 Department of Molecular and Human Genetics
43 Department of Psychiatry
44 Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford
45 USP - Universidade de São Paulo = University of São Paulo
46 Service de Pédiatrie, CHUR Poitiers
47 SNU - Seoul National University [Seoul]
48 Pediatric Neurology and Neuromuscular Diseases Unit
49 University of Manchester [Manchester]
50 YSM - Yale School of Medicine [New Haven, Connecticut]
51 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
2 Instituto Giannina Gaslini, Genoa
3 UniGe - Università degli studi di Genova = University of Genoa
4 University of Washington [Seattle]
5 Institute of Neurology, Queen Square, London
6 King‘s College London
7 UCL Institute of Neurology, Queen Square [London]
8 Genetics Research Centre - Molecular and Clinical Sciences Institute - St George’s [London, UK]
9 TAU - Tel Aviv University
10 CHU Trousseau [APHP]
11 GeneDx [Gaithersburg, MD, USA]
12 Heidelberg University Hospital [Heidelberg]
13 Royal Devon and Exeter NHS Foundation Trust [UK]
14 BNMI - Biologie Neurovasculaire et Mitochondriale Intégrée
15 CHU Angers - Centre Hospitalier Universitaire d'Angers
16 GOSH - Great Ormond Street Hospital for Children [London]
17 The University of Sydney
18 Hofstra University [Hempstead]
19 UNITO - Università degli studi di Torino = University of Turin
20 Hospital Sant Joan de Déu [Barcelona]
21 Safra Children's Hospital
22 Seoul National University Hospital
23 Central South University [Changsha]
24 Kennedy Krieger Institute [Baltimore]
25 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
26 University of Melbourne
27 Mayo Clinic [Rochester]
28 HSR - Department of Health Sciences Research [Mayo Clinic]
29 University of Ottawa [Ottawa]
30 UBC - University of British Columbia
31 UCM - Universidad Complutense de Madrid = Complutense University of Madrid [Madrid]
32 USC - Universidade de Santiago de Compostela [Spain]
33 Universiteit Leiden = Leiden University
34 ICM - Institut du Cerveau = Paris Brain Institute
35 CHU Pitié-Salpêtrière [AP-HP]
36 Università degli studi di Palermo - University of Palermo
37 Università degli studi di Trieste = University of Trieste
38 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
39 Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento
40 Children’s Hospital Colorado
41 WUSTL - Washington University in Saint Louis
42 Department of Molecular and Human Genetics
43 Department of Psychiatry
44 Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford
45 USP - Universidade de São Paulo = University of São Paulo
46 Service de Pédiatrie, CHUR Poitiers
47 SNU - Seoul National University [Seoul]
48 Pediatric Neurology and Neuromuscular Diseases Unit
49 University of Manchester [Manchester]
50 YSM - Yale School of Medicine [New Haven, Connecticut]
51 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
Estelle Colin
- Fonction : Auteur
- PersonId : 1043349
Vincent Procaccio
- Fonction : Auteur
- PersonId : 921322
Pasquale Striano
- Fonction : Auteur
- PersonId : 769112
- ORCID : 0000-0002-6065-1476
- IdRef : 200024612
Alfredo Brusco
- Fonction : Auteur
- PersonId : 895021
Enrico Del Grosso
- Fonction : Auteur
- PersonId : 1013849
Caroline Nava
- Fonction : Auteur
- PersonId : 765521
- ORCID : 0000-0003-1272-0518
Boris Keren
- Fonction : Auteur
- PersonId : 764775
- ORCID : 0000-0001-6172-8247
Henry Houlden
- Fonction : Auteur
- PersonId : 763785
- ORCID : 0000-0002-2866-7777
Yves Dauvilliers
- Fonction : Auteur
- PersonId : 1003642
Résumé
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.