Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes

作者：Berardo Rinaldi, Allan Bayat, Linda G. Zachariassen, Jiahui Sun, Yu-Han Ge, Dan Zhao, Kristine Bonde, Laura H Madsen, Ilham Abdimunim Ali Awad, Duygu Bagiran, Amal Sbeih, Syeda Maidah Shah, Shaymaa El-Sayed, Signe Meisner Lyngby, Miriam G Pedersen, Charlotte Stenum-Berg, Louise Claudia Walker, Ilona Krey, Andrée Delahaye‐Duriez, Lisa Emrick, Krystal Sully, Chaya N. Murali, Lindsay C. Burrage, Julie Ana Plaud Gonzalez, Mered Parnes, Jennifer Friedman, Bertrand Isidor, Jérémie Lefranc, Sylvia Redon, Delphine Héron, Cyril Mignot, Boris Keren, Mélanie Fradin, Christèle Dubourg, Sandra Mercier, Thomas Besnard, Benjamin Cogné, Wallid Deb, Clotilde Rivier, Donatella Milani, Maria Francesca Bedeschi, Claudia Di Napoli, Federico Grilli, Paola Marchisio, S.M. Koudijs, Danielle Veenma, Emanuela Argilli, Sally Ann Lynch, Ping Yee Billie Au, Fernando Eduardo Ayala Valenzuela, Carolyn M. Brown, Diane Masser‐Frye, Marilyn C. Jones, Leslie Patrón Romero, Wenhui Laura Li, Erin Thorpe, Laura Hecher, Jessika Johannsen, Jonas Denecke, Vanda McNiven, Anna Szuto, Emma Wakeling, Vincent Cruz, Valerie Sency, Heng Wang, Juliette Piard, Fanny Kortüm, Theresia Herget, Tatjana Bierhals, Angelo Condell, Bruria Ben Zeev, Simranpreet Kaur, John Christodoulou, Amélie Piton, Christiane Zweier, Cornelia Kraus, Alessia Micalizzi, Marina Trivisano, Nicola Specchio, Gaëtan Lesca, Rikke S. Møller, Zeynep Tümer, Maria Musgaard, Bénédicte Gérard, Johannes R. Lemke, Yun Stone Shi, Anders S. Kristensen · 发表于：Brain · 年份：2023 · DOI：10.1093/brain/awad403 · 被引用次数：28 · 研究领域：Mitochondrial Function and Pathology、Genetics and Neurodevelopmental Disorders、Congenital heart defects research

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1-GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally. Here, we evaluated the impact on AMPAR function of one frameshift and 43 rare missense GRIA3 variants identified in patients with NDD by electrophysiological assays. Thirty-one variants alter receptor function and show loss-of-function or gain-of-function properties, whereas 13 appeared neutral. We collected detailed clinical data from 25 patients (from 23 families) harbouring 17 of these variants. All patients had global developmental impairment, mostly moderate (9/25) or severe (12/25). Twelve patients had seizures, including focal motor (6/12), unknown onset motor (4/12), focal impaired awareness (1/12), (atypical) absence (2/12), myoclonic (5/12) and generalized tonic-clonic (1/12) or atonic (1/12) seizures. The epilepsy syndrome was classified as developmental and epileptic encephalopathy in eight patients, developmental encephalopathy without seizures in 13 patients, and intellectual disability with epilepsy in four patients. Limb muscular hypotonia was reported in 13/25, and hypertonia in 10/25. Movement disorders were reported in 14/25, with hyperekpl...