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 - Bettencourt, Conceicao
AU - Männikkö, Roope
AU - Manole, Andreea
AU - Brusco, Alfredo
AU - Grosso, Enrico
AU - Ferrero, Giovanni Battista
AU - Armstrong-Moron, Judith
AU - Gueden, Sophie
AU - Bar-Yosef, Omer
AU - Tzadok, Michal
AU - Monaghan, Kristin G
AU - Santiago-Sim, Teresa
AU - Person, Richard E
AU - Cho, Megan T
AU - Willaert, Rebecca
AU - Yoo, Yongjin
AU - Chae, Jong-Hee
AU - Quan, Yingting
AU - Wu, Huidan
AU - Wang, Tianyun
AU - Bernier, Raphael A
AU - Xia, Kun
AU - Blesson, Alyssa
AU - Jain, Mahim
AU - Motazacker, Mohammad M
AU - Jaeger, Bregje
AU - Iacomino, Michele
AU - Minetti, Carlo
AU - Zara, Federico
PY - 2019/7/12
Y1 - 2019/7/12
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.
KW - Adolescent
KW - Adult
KW - Brain/diagnostic imaging
KW - Child
KW - Child, Preschool
KW - Cohort Studies
KW - Female
KW - Heterozygote
KW - Humans
KW - Infant
KW - Intellectual Disability/genetics
KW - Loss of Function Mutation
KW - Magnetic Resonance Imaging
KW - Male
KW - Neurodevelopmental Disorders/diagnostic imaging
KW - Receptors, AMPA/genetics
KW - Young Adult
U2 - 10.1038/s41467-019-10910-w
DO - 10.1038/s41467-019-10910-w
M3 - Article
C2 - 31300657
VL - 10
SP - 3094
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
ER -