Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes
Standard
Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes. / Rinaldi, Berardo; Bayat, Allan; Zachariassen, Linda G; Sun, Jia-Hui; Ge, Yu-Han; Zhao, Dan; Bonde, Kristine; Madsen, Laura H; Awad, Ilham Abdimunim Ali; Bagiran, Duygu; Sbeih, Amal; Shah, Syeda Maidah; El-Sayed, Shaymaa; Lyngby, Signe M; Pedersen, Miriam G; Stenum-Berg, Charlotte; Walker, Louise Claudia; Krey, Ilona; Delahaye-Duriez, Andrée; Emrick, Lisa T; Sully, Krystal; Murali, Chaya N; Burrage, Lindsay C; Plaud Gonzalez, Julie Ana; Parnes, Mered; Friedman, Jennifer; Isidor, Bertrand; Lefranc, Jérémie; Redon, Sylvia; Heron, Delphine; Mignot, Cyril; Keren, Boris; Fradin, Mélanie; Dubourg, Christele; Mercier, Sandra; Besnard, Thomas; Cogne, Benjamin; Deb, Wallid; Rivier, Clotilde; Milani, Donatella; Bedeschi, Maria Francesca; Di Napoli, Claudia; Grilli, Federico; Marchisio, Paola; Koudijs, Suzanna; Veenma, Danielle; Argilli, Emanuela; Lynch, Sally Ann; Au, Ping Yee Billie; Ayala Valenzuela, Fernando Eduardo; Brown, Carolyn; Masser-Frye, Diane; Jones, Marilyn; Patron Romero, Leslie; Li, Wenhui Laura; Thorpe, Erin; Hecher, Laura; Johannsen, Jessika; Denecke, Jonas; McNiven, Vanda; Szuto, Anna; Wakeling, Emma; Cruz, Vincent; Sency, Valerie; Wang, Heng; Piard, Juliette; Kortüm, Fanny; Herget, Theresia; Bierhals, Tatjana; Condell, Angelo; Zeev, Bruria Ben; Kaur, Simranpreet; Christodoulou, John; Piton, Amelie; Zweier, Christiane; Kraus, Cornelia; Micalizzi, Alessia; Trivisano, Marina; Specchio, Nicola; Lesca, Gaetan; Møller, Rikke S; Tümer, Zeynep; Musgaard, Maria; Gerard, Benedicte; Lemke, Johannes R; Shi, Yun Stone; Kristensen, Anders S.
in: BRAIN, Jahrgang 147, Nr. 5, 03.05.2024, S. 1837-1855.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
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 - 2024/5/3
Y1 - 2024/5/3
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 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.
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 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.
U2 - 10.1093/brain/awad403
DO - 10.1093/brain/awad403
M3 - SCORING: Journal article
C2 - 38038360
VL - 147
SP - 1837
EP - 1855
JO - BRAIN
JF - BRAIN
SN - 0006-8950
IS - 5
ER -