Overlapping cortical malformations in patients with pathogenic variants in<i>GRIN1</i>and<i>GRIN2B</i>

Brock, Stefanie; Laquerrière, Annie; Marguet, Florent; Myers, Scott J.; Yuan, Hongjie; Baralle, Diana; Vanderhasselt, Tim; Stouffs, Katrien; Keymolen, Kathelijn; Kim, Sukhan; Allen, James P.; Shaulsky, Gil; Chelly, Jamel; Marcorelle, Pascale; Aziza, Jacqueline; Villard, Laurent; Sacaze, Elise; Wit, Marie Claire Y. de; Wilke, Martina; Mancini, Grazia M.S.; Hehr, Ute; Lim, Derek; Mansour, Sahar; Traynelis, Stephen F.; Bénéteau, Claire; Denis‐Musquer, Marie; Jansen, Anna; Fry, Andrew E.; Bahi-Buisson, Nadia

doi:10.1136/jmedgenet-2021-107971

Cited by 6 publications

(4 citation statements)

References 34 publications

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“…(Met818Thr) variant, with the GRIN2B c.2452A>C/p. (Met818Thr) variant being previously reported in patients with DEE/IESS phenotype with and without cortical malformations 53 and DD without epilepsy. 54 Functional studies suggested possible GoF 53,55 and in vitro studies and animal models suggested a potential therapeutic response to memantine.…”

Section: Dee-related To Receptors or Transporters Disordersmentioning

confidence: 85%

“…(Met818Thr) variant being previously reported in patients with DEE/IESS phenotype with and without cortical malformations 53 and DD without epilepsy 54 . Functional studies suggested possible GoF 53,55 and in vitro studies and animal models suggested a potential therapeutic response to memantine 54,56 . However, evidence of a significant favorable response to memantine in patients with GoF variants have been conflicting 57 .…”

Section: Discussionmentioning

confidence: 99%

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The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children

Elkhateeb,

Issa,

Elbendary

et al. 2024

Clinical Genetics

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Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of epilepsies characterized by early‐onset, refractory seizures associated with developmental regression or impairment, with a heterogeneous genetic landscape including genes implicated in various pathways and mechanisms. We retrospectively studied the clinical and genetic data of patients with genetic DEE who presented at two tertiary centers in Egypt over a 10‐year period. Exome sequencing was used for genetic testing. We report 74 patients from 63 unrelated Egyptian families, with a high rate of consanguinity (58%). The most common seizure type was generalized tonic–clonic (58%) and multiple seizure types were common (55%). The most common epilepsy syndrome was early infantile DEE (50%). All patients showed variable degrees of developmental impairment. Microcephaly, hypotonia, ophthalmological involvement and neuroimaging abnormalities were common. Eighteen novel variants were identified and the phenotypes of five DEE genes were expanded with novel phenotype–genotype associations. Obtaining a genetic diagnosis had implications on epilepsy management in 17 patients with variants in 12 genes. In this study, we expand the phenotype and genotype spectrum of DEE in a large single ethnic cohort of patients. Reaching a genetic diagnosis guided precision management of epilepsy in a significant proportion of patients.

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Section: Dee-related To Receptors or Transporters Disordersmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children

Elkhateeb,

Issa,

Elbendary

et al. 2024

Clinical Genetics

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“… 8 , 9 More than 350 variants of the GluN1 subunit have been identified. 10 The variants mostly occur within the ATDs, LBDs, and TMDs 8 , 11 , 12 and can result in either gain‐ or loss‐of‐function molecular phenotypes. 10 , 11 , 12 Here, we report three newly identified variants of the GluN1 subunit, which we expressed on the GluN1‐3b splice isoform for functional analysis.…”

Section: Introductionmentioning

confidence: 99%

“… 10 The variants mostly occur within the ATDs, LBDs, and TMDs 8 , 11 , 12 and can result in either gain‐ or loss‐of‐function molecular phenotypes. 10 , 11 , 12 Here, we report three newly identified variants of the GluN1 subunit, which we expressed on the GluN1‐3b splice isoform for functional analysis. The missense p. Ile148Val variant is absent from any databases and occurs within the LBD of the receptor.…”

Section: Introductionmentioning

confidence: 99%

GRIN1 variants associated with neurodevelopmental disorders reveal channel gating pathomechanisms

Ragnarsson,

Zhang,

Das

et al. 2023

Epilepsia

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ObjectiveN‐methyl‐D‐aspartate (NMDA) receptors are expressed at synaptic sites where they mediate fast excitatory neurotransmission. NMDA receptors are critical to brain development and cognitive function. Natural variants to the GRIN1 gene, which encodes the obligatory GluN1 subunit of the NMDA receptor are associated with severe neurological disorders that include epilepsy, intellectual disability and developmental delay. Here we investigated the pathogenicity of three missense variants to the GRIN1 gene, p. Ile148Val [GluN1‐3b(I481V)], p.Ala666Ser [GluN1‐3b(A666S)] and p.Tyr668His [GluN1‐3b(Y668H)].MethodsWild‐type and variant‐containing NMDA receptors were expressed in HEK293 cells and primary hippocampal neurons. Patch‐clamp electrophysiology and pharmacology was used to profile the functional properties of the receptors. Receptor surface expression was evaluated using fluorescently tagged receptors and microscopy.ResultsOur data demonstrate that the GluN1(I481V) variant is inhibited by the open pore blockers, ketamine and memantine with reduced potency but otherwise has little effect on receptor function. By contrast, the other two variants exhibit gain‐of‐function molecular phenotypes. Glycine sensitivity was enhanced in receptors containing the GluN1(A666S) variant and the potency of pore block by memantine and ketamine was reduced, whereas that for MK‐801 was increased. The most pronounced functional deficits, however, were found in receptors containing the GluN1(Y668H) variant. GluN1(Y668H)/2A receptors showed impaired surface expression, were more sensitive to glycine and glutamate by an order of magnitude and exhibited impaired block by extracellular magnesium ions, memantine, ketamine and MK‐801. These variant receptors were also activated by either glutamate or glycine alone. Single receptor recordings revealed that this receptor variant opened to several conductance levels and activated more frequently than wild‐type GluN1/2A receptors.This article is protected by copyright. All rights reserved.

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De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor

Xu,

Song,

Perszyk

et al. 2024

Cell. Mol. Life Sci.

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N-methyl-d-aspartate receptors (NMDARs) are members of the glutamate receptor family and participate in excitatory postsynaptic transmission throughout the central nervous system. Genetic variants in GRIN genes encoding NMDAR subunits are associated with a spectrum of neurological disorders. The M3 transmembrane helices of the NMDAR couple directly to the agonist-binding domains and form a helical bundle crossing in the closed receptors that occludes the pore. The M3 functions as a transduction element whose conformational change couples ligand binding to opening of an ion conducting pore. In this study, we report the functional consequences of 48 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M3 transmembrane helix. These de novo variants were identified in children with neurological and neuropsychiatric disorders including epilepsy, developmental delay, intellectual disability, hypotonia and attention deficit hyperactivity disorder. All 48 variants in M3 for which comprehensive testing was completed produce a gain-of-function (28/48) compared to loss-of-function (9/48); 11 variants had an indeterminant phenotype. This supports the idea that a key structural feature of the M3 gate exists to stabilize the closed state so that agonist binding can drive channel opening. Given that most M3 variants enhance channel gating, we assessed the potency of FDA-approved NMDAR channel blockers on these variant receptors. These data provide new insight into the structure–function relationship of the NMDAR gate, and suggest that variants within the M3 transmembrane helix produce a gain-of-function.

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Overlapping cortical malformations in patients with pathogenic variants inGRIN1andGRIN2B

Cited by 6 publications

References 34 publications

The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children

The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children

GRIN1 variants associated with neurodevelopmental disorders reveal channel gating pathomechanisms

De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor

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