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

Journal article

B. Rinaldi, Allan Bayat, L. Zachariassen, Jiahui Sun, Yu‑Han Ge, Dan Zhao, Kristine Bonde, Laura H Madsen, Ilham Abdimunim Ali Awad, Duygu Bagiran, Amal Sbeih, Syeda Maidah Shah, Shaymaa El-Sayed, Signe M. Lyngby, M. G. Pedersen, Charlotte Stenum-Berg, Louise Claudia Walker, Ilona Krey, A. Delahaye-Duriez, Lisa T. Emrick, K. Sully, C. Murali, Lindsay C Burrage, Julie Ana Plaud Gonzalez, M. Parnes, Jennifer Friedman, B. Isidor, J. Lefranc, S. Redon, Delphine Héron, C. Mignot, B. Keren, M. Fradin, C. Dubourg, S. Mercier, T. Besnard, B. Cogné, W. Deb, C. Rivier, D. Milani, M. Bedeschi, Claudia Di Napoli, Federico Grilli, Paola Marchisio, Suzanna V Koudijs, D. Veenma, E. Argilli, S. Lynch, Ping-Yee B Au, Fernando Eduardo Ayala Valenzuela, Carolyn M Brown, D. Masser-Frye, Marilyn Jones, Leslie Patron Romero, Wenhui Laura Li, Erin Thorpe, L. Hecher, J. Johannsen, J. Denecke, Vanda McNiven, A. Szuto, E. Wakeling, Vincent Cruz, Valerie Sency, Heng Wang, J. Piard, F. Kortüm, Theresia Herget, T. Bierhals, Angelo Condell, B. B. Zeev, S. Kaur, J. Christodoulou, A. Piton, C. Zweier, C. Kraus, A. Micalizzi, M. Trivisano, N. Specchio, G. Lesca, R. Møller, Z. Tümer, Maria Musgaard, B. Gérard, Johannes R. Lemke, Y. Shi, A. S. Kristensen
Brain : a journal of neurology, 2023

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APA Click to copy
Rinaldi, B., Bayat, A., Zachariassen, L., Sun, J., Ge, Y. H., Zhao, D., … Kristensen, A. S. (2023). Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes. Brain : a Journal of Neurology.

Chicago/Turabian Click to copy
Rinaldi, B., Allan Bayat, L. Zachariassen, Jiahui Sun, Yu‑Han Ge, Dan Zhao, Kristine Bonde, et al. “Gain-of-Function and Loss-of-Function Variants in GRIA3 Lead to Distinct Neurodevelopmental Phenotypes.” Brain : a journal of neurology (2023).

MLA Click to copy
Rinaldi, B., et al. “Gain-of-Function and Loss-of-Function Variants in GRIA3 Lead to Distinct Neurodevelopmental Phenotypes.” Brain : a Journal of Neurology, 2023.

BibTeX Click to copy

@article{b2023a,
  title = {Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes.},
  year = {2023},
  journal = {Brain : a journal of neurology},
  author = {Rinaldi, B. and Bayat, Allan and Zachariassen, L. and Sun, Jiahui and Ge, Yu‑Han and Zhao, Dan and Bonde, Kristine and Madsen, Laura H and Awad, Ilham Abdimunim Ali and Bagiran, Duygu and Sbeih, Amal and Shah, Syeda Maidah and El-Sayed, Shaymaa and Lyngby, Signe M. and Pedersen, M. G. and Stenum-Berg, Charlotte and Walker, Louise Claudia and Krey, Ilona and Delahaye-Duriez, A. and Emrick, Lisa T. and Sully, K. and Murali, C. and Burrage, Lindsay C and Gonzalez, Julie Ana Plaud and Parnes, M. and Friedman, Jennifer and Isidor, B. and Lefranc, J. and Redon, S. and Héron, Delphine and Mignot, C. and Keren, B. and Fradin, M. and Dubourg, C. and Mercier, S. and Besnard, T. and Cogné, B. and Deb, W. and Rivier, C. and Milani, D. and Bedeschi, M. and Napoli, Claudia Di and Grilli, Federico and Marchisio, Paola and Koudijs, Suzanna V and Veenma, D. and Argilli, E. and Lynch, S. and Au, Ping-Yee B and Valenzuela, Fernando Eduardo Ayala and Brown, Carolyn M and Masser-Frye, D. and Jones, Marilyn and Romero, Leslie Patron and Li, Wenhui Laura and Thorpe, Erin and Hecher, L. and Johannsen, J. and Denecke, J. and McNiven, Vanda and Szuto, A. and Wakeling, E. and Cruz, Vincent and Sency, Valerie and Wang, Heng and Piard, J. and Kortüm, F. and Herget, Theresia and Bierhals, T. and Condell, Angelo and Zeev, B. B. and Kaur, S. and Christodoulou, J. and Piton, A. and Zweier, C. and Kraus, C. and Micalizzi, A. and Trivisano, M. and Specchio, N. and Lesca, G. and Møller, R. and Tümer, Z. and Musgaard, Maria and Gérard, B. and Lemke, Johannes R. and Shi, Y. and Kristensen, A. S.}
}

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 (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.