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

Rinaldi B, Bayat A, Zachariassen LG, Sun JH, Ge YH, Zhao D, Bonde K, Madsen LH, Awad IAA, Bagiran D, Sbeih A, Shah SM, El-Sayed S, Lyngby SM, Pedersen MG, Stenum-Berg C, Walker LC, Krey I, Delahaye-Duriez A, Emrick LT, Sully K, Murali CN, Burrage LC, Plaud Gonzalez JA, Parnes M, Friedman J, Isidor B, Lefranc J, Redon S, Heron D, Mignot C, Keren B, Fradin M, Dubourg C, Mercier S, Besnard T, Cogne B, Deb W, Rivier C, Milani D, Bedeschi MF, Di Napoli C, Grilli F, Marchisio P, Koudijs S, Veenma D, Argilli E, Lynch SA, Au PYB, Ayala Valenzuela FE, Brown C, Masser-Frye D, Jones M, Patron Romero L, Li WL, Thorpe E, Hecher L, Johannsen J, Denecke J, McNiven V, Szuto A, Wakeling E, Cruz V, Sency V, Wang H, Piard J, Kortüm F, Herget T, Bierhals T, Condell A, Ben-Zeev B, Kaur S, Christodoulou J, Piton A, Zweier C, Kraus C, Micalizzi A, Trivisano M, Specchio N, Lesca G, Møller RS, Tümer Z, Musgaard M, Gerard B, Lemke JR, Shi YS, Kristensen AS (2024)

Publication Type: Journal article

Publication year: 2024


Book Volume: 147

Pages Range: 1837-1855

Journal Issue: 5

DOI: 10.1093/brain/awad403


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 hyperekplexia or non-epileptic erratic myoclonus being the most prevalent feature (8/25). Correlating receptor functional phenotype with clinical features revealed clinical features for GRIA3-associated NDDs and distinct NDD phenotypes for loss-of-function and gain-of-function variants. Gain-of-function variants were associated with more severe outcomes: patients were younger at the time of seizure onset (median age: 1 month), hypertonic and more often had movement disorders, including hyperekplexia. Patients with loss-of-function variants were older at the time of seizure onset (median age: 16 months), hypotonic and had sleeping disturbances. Loss-of-function and gain-of-function variants were disease-causing in both sexes but affected males often carried de novo or hemizygous loss-of-function variants inherited from healthy mothers, whereas affected females had mostly de novo heterozygous gain-of-function variants.

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Involved external institutions

Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico IT Italy (IT) University of Copenhagen DK Denmark (DK) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Hôpital Jean-Verdier FR France (FR) Texas Children's Hospital US United States (USA) (US) Baylor College of Medicine US United States (USA) (US) Nanjing University CN China (CN) Rady Children's Hospital San Diego US United States (USA) (US) Nantes University Hospital / Centre hospitalier universitaire de Nantes (CHU) FR France (FR) Centre hospitalier universitaire de Brest (CHRU Brest) FR France (FR) DDC Clinic US United States (USA) (US) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière FR France (FR) Centre hospitalier universitaire de Rennes / CHU Rennes FR France (FR) Erasmus MC - Sophia Children’s Hospital NL Netherlands (NL) Centre hospitalier régional et universitaire de Besançon (CHRU Besancon) FR France (FR) Rigshospitalet DK Denmark (DK) Hôpitaux universitaires de Strasbourg (HUS) / University Hospital Strasbourg FR France (FR) University of Ottawa CA Canada (CA) Universität Leipzig DE Germany (DE) The Hospital for Sick Children (SickKids) CA Canada (CA) Great Ormond Street Hospital (GOSH) GB United Kingdom (GB) Hospital Angeles Tijuana MX Mexico (MX) Illumina Inc US United States (USA) (US) University of California San Francisco (UCSF) US United States (USA) (US) Temple Street Children's University Hospital / Children's Health Ireland (CHI) IE Ireland (IE) Alberta Children's Hospital Research Institute (ACHRI) CA Canada (CA) Autonomous University of Baja California (UABC) MX Mexico (MX) Breakthrough Genomics US United States (USA) (US) Murdoch Childrens Research Institute AU Australia (AU) Chaim Sheba Medical Center at Tel HaShomer / המרכז הרפואי עש חיים שיבא – תל השומר‎‎ IL Israel (IL) Ospedale Pediatrico Bambino Gesu IT Italy (IT) Université Claude Bernard Lyon 1 (UCB) FR France (FR) Filadelfia DK Denmark (DK)

How to cite


Rinaldi, B., Bayat, A., Zachariassen, L.G., Sun, J.H., Ge, Y.H., Zhao, D.,... Kristensen, A.S. (2024). Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes. Brain, 147(5), 1837-1855.


Rinaldi, Berardo, et al. "Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes." Brain 147.5 (2024): 1837-1855.

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