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DOI 10.1038/s41467-019-10910-w

Медицинская библиотека · Nature communications · 2019

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

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, SYNAPS Study Group, 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

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Аннотация

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.

Для цитирования: 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, SYNAPS Study Group, 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. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.. Nature communications. 2019. DOI: 10.1038/s41467-019-10910-w.

Предметные рубрики MeSH

AdolescentAdultBrainChildChild, PreschoolCohort StudiesFemaleHeterozygoteHumansInfantIntellectual DisabilityLoss of Function MutationMagnetic Resonance ImagingMaleNeurodevelopmental DisordersReceptors, AMPAYoung Adult
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