Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy

XiangWei, Wenshu; Kannan, Varun; Xu, Yuchen; Kosobucki, Gabrielle J.; Schulien, Anthony J.; Kusumoto, Hirofumi; Achkar, Christelle Moufawad El; Bhattacharya, Subhrajit; Lesca, Gaëtan; Nguyen, Sylvie; Helbig, Ingo; Cuisset, Jean‐Marie; Fenger, Christina; Marjanović, Dragan; Schüler, Elisabeth; Wu, Ye; Bao, Xinhua; Zhang, Yuehua; Dirkx, Nina; Schoonjans, An‐Sofie; Syrbe, Steffen; Myers, Scott J.; Poduri, Annapurna; Aizenman, Elias; Traynelis, Stephen F.; Lemke, Johannes R.; Yuan, Hongjie; Jiang, Yuwu

doi:10.1093/brain/awz232

Cited by 56 publications

(78 citation statements)

References 52 publications

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“…KAR is thought to play a role in presynaptic and postsynaptic modulation of neurotransmission 36 . De novo and inherited pathogenic variations in genes encoding postsynaptic iGluRs subunits cause a wide range of NDDs and DEEs 4–10 . Interestingly, biochemical and in vitro functional assays show that variants in the same gene encoding some NMDAR and AMPAR subunits (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, biochemical and in vitro functional assays show that variants in the same gene encoding some NMDAR and AMPAR subunits (e.g. GRIN2A, GRIN2B, GRIN2D, and GRIA2 ) may act as both gain‐of‐function (GoF) and LoF and may result in indistinguishable neurological phenotypes 5–7 . This alludes to the complexity of the glutaminergic pathway with both enhanced and reduced function leading to NDDs and DEEs.…”

Section: Discussionmentioning

confidence: 99%

“…This alludes to the complexity of the glutaminergic pathway with both enhanced and reduced function leading to NDDs and DEEs. Patho‐mechanisms include alterations in any of the multiple functional parameters including agonist potency, sensitivity to negative allosteric modulators, channel opening probability, surface expression, and current amplitude response 6,7 …”

Section: Discussionmentioning

confidence: 99%

“…The iGluRs include N‐methyl‐D‐aspartate receptor (NMDAR), alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR), and kainate receptor (KAR). Rare monoallelic and biallelic single nucleotide variants (SNVs) and copy number variants (CNVs) in genes encoding postsynaptic iGluRs subunits such as GRIN1, GRIN2A , GRIN2B , and GRIN2D encoding the NR1, NR2A, NR2B, and NR2D subunits of NMDAR, respectively, GRIA2‐4 encoding the GluR2‐4 subunits of AMPAR, and GRIK2 encoding the GluR6 subunit of KAR have been shown to cause a wide range of neurodevelopmental disorders (NDDs) and DEEs 4–11 …”

Section: Introductionmentioning

confidence: 99%

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Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Marafi

Mitani

Işıkay³

et al. 2020

Ann Clin Transl Neurol

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Objective: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-proteincoupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families. Methods: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory. Results: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T: p.Arg659Ter). Developmental delay, neonatal-or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late 610 childhood. Conclusion: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Marafi

Mitani

Işıkay³

et al. 2020

Ann Clin Transl Neurol

View full text Add to dashboard Cite

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“…Unfertilized Xenopus oocytes (defolliculated Stage V‐VI) were prepared from commercially available ovaries (Xenopus 1 Inc., Dexter, MI) (XiangWei et al, ), and were injected with cRNA encoding either WT or mutant NMDAR subunits, and two‐electrode voltage‐clamp (TEVC) current recordings were performed (Chen et al, ). Briefly, cRNA (GluN1:GluN2 ratio 1:1; 5‐10 ng in 50 nl of water) was injected into each oocyte, which was maintained at 15 to 19°C in Barth's culture medium (in mM: 2.4 NaHCO 3 , 88 NaCl, 1 KCl, 0.41 CaCl 2 , 0.33 Ca(NO 3 ) 2 , 0.82 MgSO 4 , 5 HEPES; pH was adjusted to 7.4 with NaOH), plus gentamicin sulfate (0.1 mg/ml) and streptomycin (1 μg/ml).…”

Section: Methodsmentioning

confidence: 99%

De novoGRINvariants in NMDA receptor M2 channel pore‐forming loop are associated with neurological diseases

Zhang

Tang

et al. 2019

Human Mutation

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N-methyl-D-aspartate receptors (NMDARs) mediate slow excitatory postsynaptic transmission in the central nervous system, thereby exerting a critical role in neuronal development and brain function. Rare genetic variants in the GRIN genes encoding NMDAR subunits segregated with neurological disorders. Here, we summarize the clinical presentations for 18 patients harboring 12 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M2 re-entrant loop, a region that lines the pore and is intolerant to missense variation. These de novo variants were identified in children with a set of neurological and neuropsychiatric conditions. Evaluation of the receptor cell surface expression, pharmacological properties, and biophysical characteristics show that these variants can have modest changes in agonist potency, proton inhibition, and surface expression. However, voltage-dependent magnesium inhibition is significantly reduced in all variants. The NMDARs hosting a single copy of a mutant subunit showed a dominant reduction in magnesium inhibition for some variants. These variant NMDARs also show reduced calcium permeability and single-channel conductance, as well as altered open probability. The data suggest that M2 missense variants increase NMDAR charge

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Recurrent seizure‐related GRIN1 variant: Molecular mechanism and targeted therapy

Song

Chen

et al. 2021

Ann Clin Transl Neurol

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Objective: Genetic variants in the GRIN genes that encode N-methyl-Daspartate receptor (NMDAR) subunits have been identified in various neurodevelopmental disorders, including epilepsy. We identified a GRIN1 variant from an individual with early-onset epileptic encephalopathy, evaluated functional changes to NMDAR properties caused by the variant, and screened FDAapproved therapeutic compounds as potential treatments for the patient. Methods: Whole exome sequencing identified a missense variant in GRIN1. Electrophysiological recordings were made from Xenopus oocytes and transfected HEK cells to determine the NMDAR biophysical properties as well as the sensitivity to agonists and FDA-approved drugs that inhibit NMDARs. A beta-lactamase reporter assay in transfected HEK cells evaluated the effects of the variant on the NMDAR surface expression. Results: A recurrent de novo missense variant in GRIN1 (c.1923G>A, p.Met641Ile), which encodes the GluN1 subunit, was identified in a pediatric patient with drug-resistant seizures and early-onset epileptic encephalopathy. In vitro analysis indicates that GluN1-M641I containing NMDARs showed enhanced agonist potency and reduced Mg 2+ block, which may be associated with the patient's phenotype. Results from screening FDA-approved drugs suggested that GluN1-M641I containing NMDARs are more sensitive to the NMDAR channel blockers memantine, ketamine, and dextromethorphan compared to the wild-type receptors. The addition of memantine to the seizure treatment regimen significantly reduced the patient's seizure burden. Interpretation: Our finding contributes to the understanding of the phenotype-genotype correlations of patients with GRIN1 gene variants, provides a molecular mechanism underlying the actions of this variant, and explores therapeutic strategies for treating GRIN1-related neurological conditions.

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Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy

Cited by 56 publications

References 52 publications

Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

De novoGRINvariants in NMDA receptor M2 channel pore‐forming loop are associated with neurological diseases

Recurrent seizure‐related GRIN1 variant: Molecular mechanism and targeted therapy

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