{"id":13236,"date":"2024-01-04T15:03:01","date_gmt":"2024-01-04T15:03:01","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=13236"},"modified":"2024-03-15T11:33:01","modified_gmt":"2024-03-15T11:33:01","slug":"2024-functional-analysis-of-human-grin2a-mutations-associated-with-schizophrenia-and-neurodevelopmental-disorders-reveals-distinct-pathological-mechanism","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2024-functional-analysis-of-human-grin2a-mutations-associated-with-schizophrenia-and-neurodevelopmental-disorders-reveals-distinct-pathological-mechanism\/","title":{"rendered":"2024 &#8211; Functional Analysis of Human GRIN2A Mutations Associated with  Schizophrenia and Neurodevelopmental Disorders Reveals Distinct  Pathological Mechanism"},"content":{"rendered":"<p>Human genetic studies have revealed rare missense and protein-truncating variants in\u00a0<i>GRIN2A<\/i>, encoding for the GluN2A subunit of the NMDA receptors, that confer significant risk for schizophrenia (SCZ). Mutations in\u00a0<i>GRIN2A<\/i>\u00a0are also associated with epilepsy and developmental delay\/intellectual disability (DD\/ID). However, it remains enigmatic how alterations to the same protein can result in diverse clinical phenotypes. Here, we performed functional characterization of human GluN1\/GluN2A heteromeric NMDA receptors that contain SCZ-linked GluN2A variants, and compared them to NMDA receptors with GluN2A variants associated with epilepsy or DD\/ID. Our findings demonstrate that SCZ-associated\u00a0<i>GRIN2A<\/i>\u00a0variants were predominantly loss-of-function (LoF), whereas epilepsy and DD\/ID-associated variants resulted in both gain- and loss-of-function phenotypes. We additionally show that M653I and S809R, LoF\u00a0<i>GRIN2A<\/i>\u00a0variants associated with DD\/ID, exert a dominant-negative effect when co-expressed with a wild-type GluN2A, whereas E58Ter and Y698C, SCZ-linked LoF variants, and A727T, an epilepsy-linked LoF variant, do not. These data offer a potential mechanism by which SCZ\/epilepsy and DD\/ID-linked variants can cause different effects on receptor function and therefore result in divergent pathological outcomes.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,53,76],"therapeutic_areas":[55,143],"target_categories":[337],"target_families":[355],"targets":[144],"resource_keyword":[],"class_list":["post-13236","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","application_areas-assay-development-and-validation","application_areas-drug-discovery","therapeutic_areas-cns","therapeutic_areas-assay-development-and-validation","target_categories-ligand-gated-ion-channels","target_families-ionotropic-glutamate-receptors","targets-glun2a"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/13236","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=13236"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=13236"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=13236"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=13236"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=13236"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=13236"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=13236"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=13236"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=13236"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}