Expansion of the GRIA2 phenotypic representation: a novel de novo loss of function mutation in a case with childhood onset schizophrenia

Alkelai, Anna; Shohat, Shahar; Greenbaum, Lior; Schechter, Tanya; Draiman, Benjamin; Chitrit-Raveh, Eti; Rienstein, Shlomit; Dagaonkar, Neha; Hughes, Daniel; Aggarwal, Vimla S.; Heinzen, Erin L.; Shifman, Sagiv; Goldstein, David B.; Kohn, Yoav

doi:10.1038/s10038-020-00846-1

Cited by 18 publications

(15 citation statements)

References 22 publications

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“…In this case, we discovered a de novo missense variant in the GRIA2 gene, which can lead to NEDLIB (OMIM: #138247). It is also reported that the nonsense mutation of p. Glu508Ter in the GRIA2 gene leads to the occurrence of childhood onset schizophrenia (COS) ( Alkelai et al, 2021 ) ( Supplementary Table S1 ). So far, 16 missense variants of the GRIA2 gene have been reported in 20 patients, including the p. Leu645Arg discovered this time.…”

Section: Discussionmentioning

confidence: 99%

Case Report: A Novel De Novo Missense Mutation of the GRIA2 Gene in a Chinese Case of Neurodevelopmental Disorder With Language Impairment

et al. 2021

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Introduction: Neurodevelopmental disorders with language impairment and behavioral abnormalities (NEDLIB) are a disease caused by heterozygous variants in the glutamate ionotropic receptor AMPA type subunit 2 (GRIA2) gene, which manifest as impaired mental development or developmental delay, behavioral abnormalities including autistic characteristics, and language disorders. Currently, only a few mutations in the GRIA2 gene have been discovered.Methods: A GRIA2 variation was detected in a patient by whole-exome sequencing, and the site was validated by Sanger sequencing from the family.Results: We report a Chinese case of NEDLIB in a girl with language impairment and developmental delay through whole-exome sequencing (WES). Genetic analysis showed that there was a de novo missense mutation, c.1934T > G (p.Leu645Arg), in the GRIA2 gene (NM_001083619.1), which has never been reported before.Conclusion: Our case shows the potential diagnostic role of WES in NEDLIB, expands the GRIA2 gene mutation spectrum, and further deepens the understanding of NEDLIB. Deepening the study of the genetic and clinical heterogeneity, treatment, and prognosis of the disease is still our future challenge and focus.

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Section: Discussionmentioning

confidence: 99%

Case Report: A Novel De Novo Missense Mutation of the GRIA2 Gene in a Chinese Case of Neurodevelopmental Disorder With Language Impairment

et al. 2021

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“…For GRIA2, a wide variety of causative defects have been described. These include missense [7,31], nonsense [7,32], frame shift, truncation, splice site and in-frame deletion variants [7], as well as haploinsufficiency [7,[33][34][35]. Of the ten GRIA2 missense variants that have been functionally examined, six were reported to be LoF, three displayed behavior indistinguishable from that of wild-type, while one (a variant at the Q/R site) led to the production of Ca 2+ -permeable GluA2-containing receptors [7].…”

Section: Gria Disordermentioning

confidence: 99%

A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: functional characterization and targeted treatment

Coombs

Ziobro

Krotov

et al. 2022

Preprint

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AMPA-type glutamate receptors (AMPARs) are tetrameric ligand-gated ion channels formed as different combinations of GluA1-4 subunits encoded by the genes GRIA1-4. Various pathogenic variants of these genes have been described in patients with developmental delay, intellectual disability, autistic spectrum disorder and seizures. Here we report a heterozygous de novo pathogenic missense mutation in GRIA2 (c.1928 C>T, p.A643V) identified in a one-year-old male patient with seizures, developmental delay and failure to thrive. Electrophysiological investigation of heterologously expressed receptors showed GluA2 A643V to exhibit greatly slowed deactivation, and a markedly reduced extent of desensitization, compared with wild-type GluA2. When GluA2 A643V was coexpressed with the transmembrane AMPAR regulatory protein (TARP) γ2, or with both GluA1 and γ2 to generate TARPed heteromeric receptors, the slowed deactivation and decreased desensitization persisted. We found that the AMPAR negative allosteric modulator perampanel was able to fully block currents from GluA2 A643V/γ2 receptors, albeit with reduced potency compared with wild-type GluA2/γ2. The introduction of perampanel to the patient’s treatment regimen, alongside a modified Atkins diet, was associated with a marked reduction in seizure number, a resolution of failure to thrive, and clear developmental gains. Our study suggests that AMPAR gain-of-function (GoF) underlies the effect of the GRIA2 variant in our patient, and that perampanel may be beneficial in other patients with GRIA GoF variants.Author summaryRapid communication between brain cells is mediated by the excitatory neurotransmitter glutamate. Mutations affecting genes that encode glutamate-gated ion channels can result in neurodevelopmental disorders and seizures. In a young male patient, we identified a mutation in the gene responsible for production of GluA2, a key subunit of AMPA-type glutamate receptors. We showed that receptors containing GluA2 produced by this GRIA2 A643V variant were more sensitive to glutamate and gave rise to unusually prolonged or sustained responses, thus causing ‘gain-of-function’. We found that receptors affected by this mutation could, nonetheless, be inhibited by the AMPA receptor-targeting antiseizure medication, perampanel. Prompted by this finding we introduced perampanel alongside the patient’s ongoing antiseizure medication. This coincided with a decrease in the patient’s seizures and clear developmental gains. Taken together, our findings suggest that a GRIA2 gain-of-function mutation can cause neurological disease, that perampanel can be used to directly counteract the effect of the mutation, and that it may be beneficial in other GRIA gain-of-function patients.

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“…Responses to 1 ms pulse of glutamate (10 mM) were recorded with the frequency of 0.2 Hz for at least 100 traces. The average variance (σ 2 ) was calculated from all the traces and fitted with σ 2 = iI-I 2 /N + σ 0 2 where i is single channel current, I is the mean current, N is the number of available channels in the patch and σ 0 2 is the variance of background noise. The probability of opening of the receptor channels in patch at any given point in time is determined by P open = I/iN.…”

Section: Non-stationary Fluctuation Analysismentioning

confidence: 99%

“…Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate glutamate receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in brain and are encoded by the four known GRIA genes. Pathogenic variants in GRIA1, GRIA2, GRIA3, and GRIA4 have been reported in individuals with various neurodevelopmental disorders, mostly intellectual disability (ID) and autistic features [1][2][3][4]. The X-linked GRIA3 gene encodes GLUA3, one of the four pore-forming AMPAR subunits.…”

Section: Introductionmentioning

confidence: 99%

X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

et al. 2021

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The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.

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Expansion of the GRIA2 phenotypic representation: a novel de novo loss of function mutation in a case with childhood onset schizophrenia

Cited by 18 publications

References 22 publications

Case Report: A Novel De Novo Missense Mutation of the GRIA2 Gene in a Chinese Case of Neurodevelopmental Disorder With Language Impairment

Case Report: A Novel De Novo Missense Mutation of the GRIA2 Gene in a Chinese Case of Neurodevelopmental Disorder With Language Impairment

A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: functional characterization and targeted treatment

X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

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