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.
| Original language | English |
|---|---|
| Article number | 3094 |
| Journal | Nature Communications |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Dec 1 2019 |
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ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders. / SYNAPS Study Group.
In: Nature Communications, Vol. 10, No. 1, 3094, 01.12.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders
AU - SYNAPS Study Group
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 - Iacomino, Michele
AU - Minetti, Carlo
AU - Skabar, Aldo
AU - Fabretto, Antonella
AU - Cortese, Andrea
AU - Diana, Maria C.
AU - Vari, Maria S.
AU - Pedemonte, Marina
AU - Bruno, Claudio
AU - Fiorillo, Chiara
AU - Broda, Paolo
AU - Baldassari, Simona
AU - Fruscione, Floriana
AU - Madia, Francesca
AU - Traverso, Monica
AU - De-Marco, Patrizia
AU - Veggiotti, Pierangelo
AU - Marseglia, Gian L.
AU - Savasta, Salvatore
AU - Scuderi, Carmela
AU - Borgione, Eugenia
AU - Cama, Armando
AU - Capra, Valeria
AU - Coviello, Domenico A.
AU - Benfenati, Fabio
AU - Specchio, Nicola
AU - Silvestri, Gabriella
AU - Ramenghi, Luca A.
AU - Zara, Federico
PY - 2019/12/1
Y1 - 2019/12/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85068965744&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068965744&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-10910-w
DO - 10.1038/s41467-019-10910-w
M3 - Article
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3094
ER -