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

• DOI: 10.1093/brain/awad403
• Publication Date: 2023-11-30T07:11:44Z
• Authors: Berardo Rinaldi; Allan Bayat; Linda G Zachariassen; Jia-Hui Sun; Yu-Han Ge; Dan Zhao; Kristine Bonde; Laura H Madsen; Ilham Abdimunim A...; Duygu Bagiran; Amal Sbeih; Syeda Maidah Shah; Shaymaa El-Sayed; Signe M Lyngby; Miriam G Pedersen; Charlotte Stenum-...; Louise Claudia Wa...; Ilona Krey; Andrée Delahaye-D...; Lisa T Emrick; Krystal Sully; Chaya N Murali; Lindsay C Burrage; Julie Ana Plaud G...; Mered Parnes; Jennifer Friedman; Bertrand Isidor; Jérémie Lefranc; Sylvia Redon; Delphine Heron; Cyril Mignot; Boris Keren; Mélanie Fradin; Christele Dubourg; Sandra Mercier; Thomas Besnard; Benjamin Cogne; Wallid Deb; Clotilde Rivier; Donatella Milani; Maria Francesca B...; Claudia Di Napoli; Federico Grilli; Paola Marchisio; Suzanna Koudijs; Danielle Veenma; Emanuela Argilli; Sally Ann Lynch; Ping Yee Billie Au; Fernando Eduardo ...; Carolyn Brown; Diane Masser-Frye; Marilyn Jones; Leslie Patron 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; Amelie Piton; Christiane Zweier; Cornelia Kraus; Alessia Micalizzi; Marina Trivisano; Nicola Specchio; Gaetan Lesca; Rikke S Møller; Zeynep Tümer; Maria Musgaard; Benedicte Gerard; Johannes R Lemke; Yun Stone Shi; Anders S Kristensen
• Keywords: Loss function; Neurodevelopmental disorder

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 GRIA1–GRIA4 genes, which only GRIA3 is X-chromosomal. Increasing numbers missense variants are reported patients with neurodevelopmental disorders (NDD), but a few have been examined functionally. Here, we evaluated impact on AMPAR function one frameshift and 43 rare identified NDD electrophysiological assays. Thirty-one alter receptor show loss-of-function gain-of-function properties, whereas 13 appeared neutral. We collected detailed clinical data from 25 (from 23 families) harbouring 17 these variants. All had global developmental impairment, mostly moderate (9/25) severe (12/25). Twelve seizures, including focal motor (6/12), unknown onset (4/12), impaired awareness (1/12), (atypical) absence (2/12), myoclonic (5/12) generalized tonic-clonic (1/12) atonic seizures. The epilepsy syndrome was classified as epileptic encephalopathy eight patients, without seizures intellectual disability four patients. Limb muscular hypotonia 13/25, hypertonia 10/25. Movement were 14/25, hyperekplexia non-epileptic erratic myoclonus being most prevalent feature (8/25). Correlating functional phenotype features revealed for GRIA3-associated NDDs distinct phenotypes Gain-of-function associated more outcomes: younger at time seizure (median age: 1 month), hypertonic often movement disorders, hyperekplexia. Patients older 16 months), hypotonic sleeping disturbances. Loss-of-function disease-causing both sexes affected males carried de novo hemizygous inherited healthy mothers, females heterozygous