TY - JOUR

T1 - Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes

AU - Rinaldi, Berardo

AU - Bayat, Allan

AU - Zachariassen, Linda G

AU - Sun, Jia-Hui

AU - Ge, Yu-Han

AU - Zhao, Dan

AU - Bonde, Kristine

AU - Madsen, Laura H

AU - Awad, Ilham Abdimunim Ali

AU - Bagiran, Duygu

AU - Sbeih, Amal

AU - Shah, Syeda Maidah

AU - El-Sayed, Shaymaa

AU - Lyngby, Signe M

AU - Pedersen, Miriam G

AU - Stenum-Berg, Charlotte

AU - Walker, Louise Claudia

AU - Krey, Ilona

AU - Delahaye-Duriez, Andrée

AU - Emrick, Lisa T

AU - Sully, Krystal

AU - Murali, Chaya N

AU - Burrage, Lindsay C

AU - Plaud Gonzalez, Julie Ana

AU - Parnes, Mered

AU - Friedman, Jennifer

AU - Isidor, Bertrand

AU - Lefranc, Jérémie

AU - Redon, Sylvia

AU - Heron, Delphine

AU - Mignot, Cyril

AU - Keren, Boris

AU - Fradin, Mélanie

AU - Dubourg, Christele

AU - Mercier, Sandra

AU - Besnard, Thomas

AU - Cogne, Benjamin

AU - Deb, Wallid

AU - Rivier, Clotilde

AU - Milani, Donatella

AU - Bedeschi, Maria Francesca

AU - Di Napoli, Claudia

AU - Grilli, Federico

AU - Marchisio, Paola

AU - Koudijs, Suzanna

AU - Veenma, Danielle

AU - Argilli, Emanuela

AU - Lynch, Sally Ann

AU - Au, Ping Yee Billie

AU - Ayala Valenzuela, Fernando Eduardo

AU - Brown, Carolyn

AU - Masser-Frye, Diane

AU - Jones, Marilyn

AU - Patron Romero, Leslie

AU - Li, Wenhui Laura

AU - Thorpe, Erin

AU - Hecher, Laura

AU - Johannsen, Jessika

AU - Denecke, Jonas

AU - McNiven, Vanda

AU - Szuto, Anna

AU - Wakeling, Emma

AU - Cruz, Vincent

AU - Sency, Valerie

AU - Wang, Heng

AU - Piard, Juliette

AU - Kortüm, Fanny

AU - Herget, Theresia

AU - Bierhals, Tatjana

AU - Condell, Angelo

AU - Zeev, Bruria Ben

AU - Kaur, Simranpreet

AU - Christodoulou, John

AU - Piton, Amelie

AU - Zweier, Christiane

AU - Kraus, Cornelia

AU - Micalizzi, Alessia

AU - Trivisano, Marina

AU - Specchio, Nicola

AU - Lesca, Gaetan

AU - Møller, Rikke S

AU - Tümer, Zeynep

AU - Musgaard, Maria

AU - Gerard, Benedicte

AU - Lemke, Johannes R

AU - Shi, Yun Stone

AU - Kristensen, Anders S

N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

PY - 2024

Y1 - 2024

N2 - 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 (LoF) or gain-of-function (GoF) 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 LoF and GoF variants. GoF variants were associated with more severe outcomes: patients were younger at the time of seizure onset (median age one month), hypertonic, and more often had movement disorders, including hyperekplexia. Patients with LoF variants were older at the time of seizure onset (median age 16 months), hypotonic, and had sleeping disturbances. LoF and GoF variants were disease-causing in both sexes but affected males often carried de novo or hemizygous LoF variants inherited from healthy mothers, whereas all but one affected females had de novo heterozygous GoF variants.

AB - 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 (LoF) or gain-of-function (GoF) 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 LoF and GoF variants. GoF variants were associated with more severe outcomes: patients were younger at the time of seizure onset (median age one month), hypertonic, and more often had movement disorders, including hyperekplexia. Patients with LoF variants were older at the time of seizure onset (median age 16 months), hypotonic, and had sleeping disturbances. LoF and GoF variants were disease-causing in both sexes but affected males often carried de novo or hemizygous LoF variants inherited from healthy mothers, whereas all but one affected females had de novo heterozygous GoF variants.

U2 - 10.1093/brain/awad403

DO - 10.1093/brain/awad403

M3 - Journal article

C2 - 38038360

JO - Brain

JF - Brain

SN - 0006-8950

ER -