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

2019-07-12

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

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

Houlden, Henry

Journal Article

0000-0001-5701-8365

0000-0003-4900-9877

0000-0002-1119-6809

0000-0003-4530-4537

0000-0001-5790-1051

0000-0001-9567-649X

0000-0001-9090-7690

0000-0002-8727-9184

0000-0002-8318-7231

0000-0001-5260-7187

0000-0002-9420-085X

0000-0002-7222-9985

0000-0002-8059-6064

0000-0002-9195-1455

0000-0002-8246-4014

0000-0001-6696-3545

0000-0002-2866-7777

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.

link

Nature Communications 2019; 10(1): 3094

Nature Communications