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

Journal

Book Volume: 147

Pages Range: 1837-1855

Journal Issue: 5

DOI: 10.1093/brain/awad403

Abstract

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.

Authors with CRIS profile

Involved external institutions

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

How to cite

APA:

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. https://doi.org/10.1093/brain/awad403

MLA:

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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