GRIN2A Mutations Research Articles

GRIN2A and Schizophrenia: Scientific Evidence and Biological Mechanisms.

Schizophrenia is a severe psychiatric disorder and a complex polygenic inherited disease that affects nearly 1% of the global population. Although considerable progress has been made over the past 10 years in the treatment of schizophrenia, antipsychotics are not universally effective and may have serious side effects. The hypofunction of glutamate NMDA receptors (NMDARs) in GABAergic interneurons has long been postulated to be the principal pathophysiology of schizophrenia. A recent study has shown that GRIN2A pathogenic variants are closely related to the aetiology of the disorder. GRIN2A encodes the GluN2A protein, which is a subunit of NMDAR. Most GRIN2A variants have been predicted to cause protein truncation, which results in reduced gene expression. Preclinical studies have indicated that GRIN2A mutations lead to NMDAR loss of function and substantially increase the risk of schizophrenia; however, their role in schizophrenia is not well understood. We hypothesise that the heterozygous loss of GRIN2A induces NMDAR hypofunction sufficient to confer a substantial risk of schizophrenia. Therefore, this review focuses on GRIN2A as a target for novel antipsychotics and discusses the mechanisms by which GRIN2A modulates antischizophrenic activities. Moreover, our review contributes to the understanding of the pathophysiology of schizophrenia to facilitate finding treatments for the cognitive and negative symptoms of schizophrenia.

Spitz melanoma with MAP3K8::ABLIM1 rearrangement: a case report with review of the literature

BackgroundSpitz tumors are relatively uncommon melanocytic lesions, typically affecting a relatively younger population but can be encountered at any age. They are characterized by a proliferation of melanocytes with epithelioid and/or spindled cytomorphology features, and interpretation is often challenging. The majority of these tumors are driven by kinase fusions or HRAS mutations. MAP3K8 fusions, although rare, are characteristic genomic events in Spitz tumors, especially in more atypical or malignant lesions.Case presentationHere, we present the case of a 43-year-old woman with a clinically cystic mass in her right groin, histologically characterized as a spindle and epithelioid cell malignant tumor. Immunohistochemistry revealed diffuse expression of S100 protein, tyrosinase and SOX10, patchy weak PRAME, HMB45 and Melan-A reactivity, and negative staining for BRAF V600E. Next-generation sequencing analysis revealed the presence of a MAP3K8::ABLIM1 fusion gene, as well as GRIN2A and TERT promoter mutations. The morphology, immunohistochemistry and molecular analysis confirmed Spitz melanoma with molecular features suggesting a worse prognosis.ConclusionThis case introduces a novel fusion partner of MAP3K8 in the context of Spitz melanoma and expands the morphologic and molecular spectrum of Spitz melanoma.

Molecular characteristics of dedifferentiated liposarcoma with broad rhabdomyosarcomatous differentiation.

e23530 Background: Dedifferentiated liposarcoma (DDLPS) with broad rhabdomyosarcomatous differentiation has a worse prognosis compared with other types of DDLPS. Therefore, it is of importance to recognize its molecular characteristics in order to investigate individualized treatment strategies. Methods: We conduct next-generation sequencing (NGS) including DNA and RNA sequencing analysis in 5 DDLPS patients with broad rhabdomyosarcomatous differentiation and perform comparative analysis between well-differentiated and dedifferentiated components from the patients. Results: In the ten samples, several somatic copy-number variations (CNVs) including the gain of 12q are considered as frequent molecular alterations. IGFN1, FGFR4, BLM, RICTOR, RUNX1 and TOP1 mutation is the high-frequency single-nucleotide variations (SNVs). Novel BEST3/CD63/LGR5/CENPL-MDM2 and ERBB3-TAFA2 fusion genes are identified in this subtype of tumor. The comparative analysis between well-differentiated and dedifferentiated components recognized two categories of molecular variations: shared variations, such as FGFR4 and BLM mutation, ERBB3-TAFA2 fusion, and MYC amplification that are associated with tumorigenesis, and dedifferentiated-specific variations including GRIN2A, FOXP1 and TP53 mutation, CERS4-PTPRB and TRIO-TERT fusion, and ESR1 amplification, which are related with malignant progression. After surgery, the patient received adjuvant therapy. The mean follow-up of the patients was 30 months, and the mean recurrence-free survival (RFS) was 9.6 months. Conclusions: This NGS analysis disclosed the possible progression mechanisms and therapeutic targets in DDLPS with broad rhabdomyosarcomatous differentiation and provided insights contributing to the refinement of management in this tumor. [Table: see text]

Postoperative ctDNA in indicating the recurrence risk and monitoring the effect of adjuvant therapy in surgical non-small cell lung cancer.

Circulating tumor DNA (ctDNA) has emerged as a potential novel biomarker to predict molecular residual disease (MRD) in lung cancer after definitive treatment. Herein, we investigated the value of ctDNA in prognosing risk of relapse and monitoring the effect of adjuvant therapy in surgical non-small cell lung cancer (NSCLC). We enrolled 58 NSCLC patients in a real-world setting, and 58 tumor tissues and 325 plasma samples were analyzed. Tumor tissues and plasma samples were subjected to targeted next-generation sequencing (NGS) of 1021 cancer-related and ultra-deep targeted NGS covering 338 genes, respectively. ctDNA was detected in 31.0% of cases at the first postoperative time, which was associated with advanced tumor stage, T stage and KEAP1 or GRIN2A mutations in tissues. ctDNA positivity at landmark and longitudinal indicated the shorter disease-free survival. For patients with ctDNA positivity at the first postoperative time, regardless of adjuvant therapy, all patients who were persistently ctDNA positive during postoperative surveillance had disease recurrence. Among the patients who were ctDNA negative, only two patients (15.4%, 2/13) receiving adjuvant therapy relapsed, while one patient (50.0%, 1/2) without adjuvant therapy relapsed. For the first postoperative ctDNA negative patients, the recurrence rate of patients with adjuvant therapy was and higher than without adjuvant therapy (22.6% [7/31] vs. 11.1% [1/9]). The patients who became ctDNA positive may also benefit from intervention therapy. Postoperative ctDNA is a prognostic marker, and ctDNA-detection may facilitate personalized adjuvant therapy, and applying adjuvant therapy to the patients with detectable ctDNA could bring clinical benefits for them.

Differential functional consequences of GRIN2A mutations associated with schizophrenia and neurodevelopmental disorders

Human genetic studies have revealed rare missense and protein-truncating variants in GRIN2A, encoding for the GluN2A subunit of the NMDA receptors, that confer significant risk for schizophrenia (SCZ). Mutations in GRIN2A are also associated with epilepsy and developmental delay/intellectual disability (DD/ID). However, it remains enigmatic how alterations to the same protein can result in diverse clinical phenotypes. Here, we performed functional characterization of human GluN1/GluN2A heteromeric NMDA receptors that contain SCZ-linked GluN2A variants, and compared them to NMDA receptors with GluN2A variants associated with epilepsy or DD/ID. Our findings demonstrate that SCZ-associated GRIN2A variants were predominantly loss-of-function (LoF), whereas epilepsy and DD/ID-associated variants resulted in both gain- and loss-of-function phenotypes. We additionally show that M653I and S809R, LoF GRIN2A variants associated with DD/ID, exert a dominant-negative effect when co-expressed with a wild-type GluN2A, whereas E58Ter and Y698C, SCZ-linked LoF variants, and A727T, an epilepsy-linked LoF variant, do not. These data offer a potential mechanism by which SCZ/epilepsy and DD/ID-linked variants can cause different effects on receptor function and therefore result in divergent pathological outcomes.

Brain-region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice

A genetically valid animal model could transform our understanding of schizophrenia (SCZ) disease mechanisms. Rare heterozygous loss-of-function (LoF) mutations in GRIN2A, encoding a subunit of the NMDA receptor, greatly increase the risk of SCZ. By transcriptomic, proteomic, and behavioral analyses, we report that heterozygous Grin2a mutant mice show (1) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes and oligodendrocytes), (2) evidence of hypoactivity in the prefrontal cortex (PFC) and hyperactivity in the hippocampus and striatum, (3) an elevated dopamine signaling in the striatum and hypersensitivity to amphetamine-induced hyperlocomotion (AIH), (4) altered cholesterol biosynthesis in astrocytes, (5) a reduction in glutamatergic receptor signaling proteins in the synapse, and (6) an aberrant locomotor pattern opposite of that induced by antipsychotic drugs. These findings reveal potential pathophysiologic mechanisms, provide support for both the "hypo-glutamate" and "hyper-dopamine" hypotheses of SCZ, and underscore the utility of Grin2a-deficient mice as a genetic model of SCZ.

Language deficits in GRIN2A mutations and Landau–Kleffner syndrome as neural dysrhythmias

Language deficits in GRIN2A mutations and Landau–Kleffner syndrome as neural dysrhythmias

Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients

Schizophrenia is a heterogeneous psychiatric disorder with a strong genetic basis, whose etiology and pathophysiology remain poorly understood. Exome sequencing studies have uncovered rare, loss-of-function variants that greatly increase risk of schizophrenia [1], including loss-of-function mutations in GRIN2A (aka GluN2A or NR2A, encoding the NMDA receptor subunit 2A) and AKAP11 (A-Kinase Anchoring Protein 11). AKAP11 and GRIN2A mutations are also associated with bipolar disorder [2], and epilepsy and developmental delay/intellectual disability [1, 3, 4], respectively. Accessible in both humans and rodents, electroencephalogram (EEG) recordings offer a window into brain activity and display abnormal features in schizophrenia patients. Does loss of Grin2a or Akap11 in mice also result in EEG abnormalities? We monitored EEG in heterozygous and homozygous knockout Grin2a and Akap11 mutant mice compared with their wild-type littermates, at 3- and 6-months of age, across the sleep/wake cycle and during auditory stimulation protocols. Grin2a and Akap11 mutants exhibited increased resting gamma power, attenuated auditory steady-state responses (ASSR) at gamma frequencies, and reduced responses to unexpected auditory stimuli during mismatch negativity (MMN) tests. Sleep spindle density was reduced in a gene dose-dependent manner in Akap11 mutants, whereas Grin2a mutants showed increased sleep spindle density. The EEG phenotypes of Grin2a and Akap11 mutant mice show a variety of abnormal features that overlap considerably with human schizophrenia patients, reflecting systems-level changes caused by Grin2a and Akap11 deficiency. These neurophysiologic findings further substantiate Grin2a and Akap11 mutants as genetic models of schizophrenia and identify potential biomarkers for stratification of schizophrenia patients.

Abstract 5251: GRIN2A mutations as potential positive predictor for response of immune checkpoint inhibitors in melanoma

Abstract Background: Melanoma is a serious skin cancer. Immune checkpoint inhibitors (ICIs) including atezolizumab, pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. Studies have shown that Tumor Mutation Burden (TMB) was significantly (p < 0.001) associated with mutations in genes like GRIN2A in Non-Small Cell Lung Cancer (NSCLC), which means that the mutation of GRIN2A gene may be related to the efficacy of immunotherapy in patients with NSCLC, but the association between GRIN2A mutation and TMB or survival in melanoma is unknown. Methods: The association between GRIN2A mutation with TMB and survival data was analyzed in melanoma patients from the public immunotherapy-treated cohort called Miao2018.Pancancer.249.WES, which worked as training cohort while the validation cohort was retrieved from Melanoma.Allen2015.WES.110. Wilcoxon test was used for the comparison of TMB and Tumor Neoantigen Burden (TNB). Progress Free Survival (PFS):Overall survival (OS) analyses were conducted in the public cohort using Kaplan-Meier curves and log-rank tests. Statistical significance was set at p=0.05. Results: In the training cohort, 33.8% (51/151) melanoma patients harbored GRIN2A mutation. GRIN2A mutation is associated with higher TMB (p<0.001) and higher TNB (p<0.001). Survival analysis demonstrated that GRIN2A mutation resulted in significantly longer PFS (5.6 vs 3.3months; HR, 0.58; p=0.027) and longer OS (22.5 vs 12.8 months; HR, 0.61; p=0.039) in melanoma patients treated with ICIs. While validation cohort1 showed that 22.7% (25/110) melanoma patients harbored GRIN2A mutation and GRIN2A mutation resulted in an increasing trend on TMB with strongly significant difference (p<0.001) and significantly longer OS (22.5 vs 8.3months; HR, 0.53; p=0.025). Conclusions: This study shows that GRIN2A mutation is correlated with higher TMB and TNB in melanoma and serve as a predictive biomarker of ICI benefit in melanoma. Citation Format: Ling Ye, Dandan Fan, Yaoxu Chen, Mengli Huang. GRIN2A mutations as potential positive predictor for response of immune checkpoint inhibitors in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5251.

Abstract 5094: A pan-cancer analysis of GRIN2A as a potential biomarker for immune checkpoint therapy

Abstract Background: GRIN2A is the encoding gene of GluN2A, which is a subunit of the N-methyl-D-aspartate receptor, and participates in the regulation of excitatory neurotransmission in the brain. GRIN2A is one of the key genes in epilepsy researches, however, only a few researches have been done on GRIN2A in cancer field. The existing studies showed that GRIN2A mutation was frequently found in melanoma and caused abnormal tumor suppressor function. Besides, GRIN2A mutation was associated with higher tumor mutation burden (TMB) in non-small-cell lung cancer, suggesting that GRIN2A-altered tumors might be more sensitive to immune checkpoint inhibitors (ICIs), but the correlation of GRIN2A mutation status with immune response in clinical remains unknown. Methods: Next generation sequencing (NGS) and clinical data of pan-cancer patients were obtained from two MSK-IMPACT Clinical Sequencing cohorts (MSK-2017, N=10336; MSK-2019, N=1661). The MSK-2019 cohort, which was treated with ICIs, were analyzed to explore the association between GRIN2A alteration and therapeutic efficacy of ICIs. Moreover, mRNA expression data of 10201 pan-cancer patients were obtained from the Cancer Genome Atlas (TCGA) database to explore the association between GRIN2A expression level and immune cell infiltration. Results: In total, 3.74% (387/10336) of pan-cancer patients in MSK-2017, and 7.47% (124/1661) in MSK-2019, carried GRIN2A alteration. In MSK-2017, the top three GRIN2A alteration frequency cancer types were melanoma (68/365, 18.63%), skin cancer (non-melanoma, 22/148, 14.86%) and small cell lung cancer (11/82, 13.41%), respectively. And the commonly mutation types of GRIN2A were missense mutation. In MSK-2019 treated with ICIs, the TMB level of GRIN2A-altered group was significantly higher than wild group (median TMB, altered-type vs. wild-type = 25.09 vs. 5.90 Muts/Mb, P<0.0001) and the overall survival (OS) of GRIN2A-altered group were significantly longer than wild group (OS, median, 44.00 vs. 15.00 months; HR=0.5812 [95%CI: 0,4474-0.7550], P=0.0008). But in MSK-2017 without immunotherapy, there was no difference in OS between GRIN2A-altered group and wild group (OS, median, 26.00 vs. 26.13 months; HR=1.194 [95%CI: 0.9588-1.487], P=0.0849). Furthermore, the GRIN2A expression level was positively correlated with the degree of immune cell infiltration in some tumor types, such as prostate adenocarcinoma (PRAD), while some tumors did the opposite, such as sarcoma (SARC). Conclusion: The results indicated that GRIN2A gene alteration was associated with a higher TMB level in pan-cancer patients, and patients carrying GRIN2A alteration might easily benefit from ICIs. Citation Format: Mei Jiang, Xuefeng Zhong, Mengli Huang. A pan-cancer analysis of GRIN2A as a potential biomarker for immune checkpoint therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5094.

The GluN2A Subunit of the NMDA Receptor Modulates the Rate of Functional Maturation in Parvalbumin‐positive Interneurons

N‐methyl‐D‐aspartate receptors are glutamate‐gated, calcium‐permeable ion channels involved in a host of normal brain functions, including neuronal development. Traditionally, the GluN2A subunit, encoded by the GRIN2A gene, is thought to signal brain and circuit maturation, given its unique expression pattern where transcripts are low embryonically and then significantly increase during preadolescence in mice. Advances in whole exome sequencing have identified mutations in the GRIN2A gene to be causal to several neuropathological diseases, including epilepsy and intellectual delay. More specifically, 56% of GRIN2A mutations are loss‐of‐function, displaying diminished receptor function and/or surface expression, with Grin2a­‐/‐ mice have been reported as having signatures of epileptiform activity. However, little is understood regarding GluN2A’s impact on neurodevelopmental and how its absence may the GABAergic interneuron network. Our data show that Grin2a ‐/‐ mice contain 33% more parvalbumin+ interneurons in the CA1 region of the hippocampus during preadolescence and adulthood. This increase in GABAergic interneuron cell density appears to be unique to parvalbumin+ cells, as cholecystokinin+ and somatostatin+ interneurons are unchanged across Grin2a‐/‐ and wildtype mice. Despite an increased cell count, colocalization staining for parvalbumin+ synaptic densities and measures of parvalbumin cell‐specific tonic inhibition remains unchanged in preadolescence and increases as the animal ages, suggesting delayed maturation. In addition, parvalbumin+ cells from preadolescent Grin2a‐/‐ mice exhibit immature intrinsic and firing properties, such as an increased membrane time constant and input resistance, lower threshold for depolarization‐induced block, and longer action potential half‐widths than age‐matched WT controls, all of which become corrected in adulthood. The sum of these data suggest that the GluN2A subunit is involved in promoting cues for interneuron apoptosis during development, as well as influencing the rate of parvalbumin+ cell functional maturation. The ramifications of these abnormalities are still underexplored, but likely generate a vulnerability time window during preadolescence in which an epileptiform network can manifest. Viral strategies aimed at reintroduction of the GRIN2A gene during this critical time window could represent a viable gene therapy option for loss‐of‐function GRIN2A EE patients.

Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A

Dominant mutations in the human gene GRIN2A, encoding NMDA receptor (NMDAR) subunit GluN2A, make a significant and growing contribution to the catalogue of published single-gene epilepsies. Understanding the disease mechanism in these epilepsy patients is complicated by the surprising diversity of effects that the mutations have on NMDARs. Here we have examined the cell-autonomous effect of five GluN2A mutations, 3 loss-of-function and 2 gain-of-function, on evoked NMDAR-mediated synaptic currents (NMDA-EPSCs) in CA1 pyramidal neurons in cultured hippocampal slices. Despite the mutants differing in their functional incorporation at synapses, prolonged NMDA-EPSC current decays (with only marginal changes in charge transfer) were a common effect for both gain- and loss-of-function mutants. Modelling NMDA-EPSCs with mutant properties in a CA1 neuron revealed that the effect of GRIN2A mutations can lead to abnormal temporal integration and spine calcium dynamics during trains of concerted synaptic activity. Investigations beyond establishing the molecular defects of GluN2A mutants are much needed to understand their impact on synaptic transmission.

Abstract PO-221: Racial differences in frequently mutated protein-coding genes correlates with survival, invasion and metastasis in colorectal cancer

Abstract Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States. CRC is caused by mutation in oncogenes, tumor suppressor genes, and genes associated with metastasis and invasion. Understanding mutational signatures in CRC will provide an insight into a specific developmental pathway and pave the way for targeted therapy. Thus, preventing disparity in CRC treatment among racial and ethnic groups. This study aimed to determine the distinct and commonly mutated protein-coding genes of CRC in Whites, African-American and Asian and to evaluate their correlation with survival, invasion and metastasis in CRC. Method: The Cancer Genome Atlas Research Network (TCGA), March, 2021 database on the genomic data commons data portal was queried for frequently mutated protein coding genes. The search was carried out on male and female (ages 34 to 90) colorectal cancer cases in Whites, African-Americans and Asians. The protein coding genes queried are APC, TP53, KRAS, PIK3CA, FAT4, KMT2D, RNF213, ARIDIA, BRAF, TET2, ATM, ZFHX3, FAT1, AMER1, NCOR2, FBXW7, SMAD4, TCFTL2, MYH9, CREBBP, KMT2C, CTNNB1, NRG1, ARAD1B, RNF 43, NF 1, MLLT 4, NIN, KDR, EP 300, PDGFRH, RHOH, ZNF521, MED12, GRIN2A, MECOM and RPL5. Racial differences in protein coding genes in CRC were evaluated using cluster and radar analysis and correlation study for CRC survival, invasion and metastasis pathway were carried using the Pearson correlation with NCSS statistical software. Results: Mutation in APC, TP53, KRAS, PIK3CA, FAT4 and TET-2 with high correlation with inflammation, cell death and survival were common for Whites, African Americans and Asians. African Americans showed distinctive mutation in KMT2C, CTNNB1, NRG1, ARAD1B, RNF 43, NF 1 and MLLT 4 which shows highly positive correlation with proliferation, epithelial mesenchymal transition, adhesion and metastasis. Mutations in NIN, KDR, EP 300, PDGFRH, RHOH, ZNF521, MED12, GRIN2A, MECOM and RPL5 which correlated with cell proliferation and apoptosis was specific for Asians whereas Whites show specific mutation for ARIDIA, TCFTL2 and MYH9 that correlated with chromatin remodeling, hormone function, and cell adhesion. The only mutated gene associated with Black and Asian alone was RNF 43 while Asian and Whites shared mutation in BRAF, ATM and SMAD4. Furthermore, a high level of similarity in mutation was observed for RNF 43, ZFHX3, FAT1, AMER1, FBXW7 and CREBBP. In Conclusion, the racial differences in pathway-based analysis of protein coding genes mutated in colorectal cancer have provided an emerging biomarkers for targeted therapies and chemoprevention of colorectal cancer, thus providing a solution to racial and ethnic disparities associated with cancer treatment and prevention. Citation Format: Babajide Oluwaseun Ajayi, Anuoluwapo Adejoke Adeshina. Racial differences in frequently mutated protein-coding genes correlates with survival, invasion and metastasis in colorectal cancer [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-221.

GRIN2A Variants Associated With Idiopathic Generalized Epilepsies.

Objective: The objective of this study is to explore the role of GRIN2A gene in idiopathic generalized epilepsies and the potential underlying mechanism for phenotypic variation.Methods: Whole-exome sequencing was performed in a cohort of 88 patients with idiopathic generalized epilepsies. Electro-physiological alterations of the recombinant N-methyl-D-aspartate receptors (NMDARs) containing GluN2A mutants were examined using two-electrode voltage-clamp recordings. The alterations of protein expression were detected by immunofluorescence staining and biotinylation. Previous studies reported that epilepsy related GRIN2A missense mutations were reviewed. The correlation among phenotypes, functional alterations, and molecular locations was analyzed.Results: Three novel heterozygous missense GRIN2A mutations (c.1770A > C/p.K590N, c.2636A > G/p.K879R, and c.3199C > T/p.R1067W) were identified in three unrelated cases. Electrophysiological analysis demonstrated R1067W significantly increased the current density of GluN1/GluN2A NMDARs. Immunofluorescence staining indicated GluN2A mutants had abundant distribution in the membrane and cytoplasm. Western blotting showed the ratios of surface and total expression of the three GluN2A-mutants were significantly increased comparing to the wild type. Further analysis on the reported missense mutations demonstrated that mutations with severe gain-of-function were associated with epileptic encephalopathy, while mutations with mild gain of function were associated with mild phenotypes, suggesting a quantitative correlation between gain-of-function and phenotypic severity. The mutations located around transmembrane domains were more frequently associated with severe phenotypes and absence seizure-related mutations were mostly located in carboxyl-terminal domain, suggesting molecular sub-regional effects.Significance: This study revealed GRIN2A gene was potentially a candidate pathogenic gene of idiopathic generalized epilepsies. The functional quantitative correlation and the molecular sub-regional implication of mutations helped in explaining the relatively mild clinical phenotypes and incomplete penetrance associated with GRIN2A variants.

GRIN2A and GRIN2B and Their Related Phenotypes

AbstractGlutamate is the most relevant excitatory neurotransmitter of the central nervous system; it binds with several receptors, including N-methyl-D-aspartate receptors (NMDARs), a subtype of ionotropic glutamate receptor that displays voltage-dependent block by Mg2+ and a high permeability to Ca2+. GRIN2A and GRIN2B genes encode the GluN2A and GluN2B subunits of the NMDARs, which play important roles in synaptogenesis, synaptic transmission, and synaptic plasticity, as well as contributing to neuronal loss and dysfunction in several neurological disorders. Recently, individuals with a range of childhood-onset drug-resistant epilepsies, such as Landau–Kleffner or Lennox–Gastaut syndrome, intellectual disability (ID), and other neurodevelopmental abnormalities have been found to carry mutations in GRIN2A and GRIN2B, with high variable expressivity in phenotype. The first one is found mainly in epilepsy-aphasia syndromes, while the second one mainly in autism, schizophrenia, and ID, such as autism spectrum disorders. Brain magnetic resonance imaging alterations are found in some patients, even if without a clear clinical correlation. At the same time, increasing data on genotype–phenotype correlation have been found, but this is still not fully demonstrated. There are no specific therapies for the treatment of correlated NMDARs epilepsy, although some evidence with memantine, an antagonist of glutamate receptor, is reported in the literature in selected cases with mutation determining a gain of function.

Distinct Genomic Landscape of Colorectal Mucinous Carcinoma Determined via Comprehensive Genomic Profiling: Steps to a New Treatment Strategy.

Colorectal mucinous carcinoma (MC) is associated with inferior prognosis and response to treatment compared to adenocarcinoma (AC). The molecular landscapes of MC and adenocarcinoma with mucous composition (AMC) are not well-defined. We aimed to describe the genomic landscape of MC and AMC in a large colorectal cancer cohort. Tumor samples from patients with MC, AMC, or AC were analyzed using next-generation sequencing. MC had a molecular signature distinct from that of AC; genomic features were similar between AMC and MC but not between AMC and AC. HER2 amplification and TP53 and APC mutation rates were lower, whereas SMAD4, PIK3CA, ACVR2A, KMT2D, LRP1, TGFBR2, GRIN2A, BRAF V600E, PTEN, and BRCA2 mutation rates were higher in MC than in AC. The mutation frequencies in MAPK, PI3K, and TGF- pathways were higher, whereas those of cell cycle proteins and Wnt were lower in MC and AMC than in AC. The proportion of hypermutated tumors was significantly higher in MC and AMC than in AC. As MC has a distinct molecular signature from AC, immunotherapy can be potentially applied in treating MC. Similar molecular profiles of AMC and MC suggest that treatment strategies for MC, but not AC, can be used for AMC treatment.

Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs.

PurposeCirculating cell-free DNA (cfDNA) level has been demonstrated to be associated with efficacy in first generation EGFR TKIs in non-small cell lung cancer (NSCLC). However, the role of dynamic cfDNA analysis using next-generation sequencing (NGS) in patients with subsequent third-generation EGFR TKIs remains unclear.MethodsFrom 2016 to 2019, 81 NSCLC patients with EGFR T790M mutation either in tissue or plasma who received third-generation EGFR TKIs treatment were enrolled. CfDNA were sequenced by NGS with a 425-gene panel. The association of clinical characteristics, pretreatment, dynamic cfDNA and T790M level with outcomes in patients treated with the third-generation TKIs were analyzed.ResultsIn univariate analysis, the median PFS of patients with undetectable cfDNA level during treatment was significantly longer than those with detectable cfDNA (16.97 vs. 6.10 months; HR 0.2109; P < 0.0001). The median PFS of patients with undetectable T790M level during treatment was significantly longer than those with detectable T790M (14.1 vs. 4.4 months; HR 0.2192; P < 0.001). Cox hazard proportion model showed that cfDNA clearance was an independent predictor for longer PFS (HR 0.3085; P < 0.001) and longer OS (HR 0.499; P = 0.034). The most common resistant mutations of the third-generation TKIs were EGFR C797S (24%). CDK6 CNV, GRIN2A, BRCA2, EGFR D761N, EGFR Q791H, EGFR V843I, and ERBB4 mutation genes may possibly be new resistant mechanisms.ConclusionsPatients with undetectable cfDNA during the third-generation EGFR TKI treatment have superior clinical outcomes, and dynamic cfDNA analysis by NGS is valuable to explore potential resistant mechanisms.

Infantile hemiconvulsion-hemiplegia epilepsy syndrome associated with GRIN2A gene mutation

Introduction. Infantile hemiconvulsion?hemiplegia and epilepsy (IHHE) syndrome is defined as a specific syndrome in patients &lt; 2 years of age, presenting as a new onset refractory status epilepticus with unilateral motor seizures and acute imaging abnormalities, fever, hemiparesis &gt; 24 hours, and excluding infectious encephalitis. Case outline. We present the results of a follow-up in a 11-year-old girl with IHHE, associated with GRIN2A mutation. The girl had normal development until the first febrile hemiconvulsive status epilepticus at the age of seven months. Neuroimaging initially showed right hemisphere edema, followed by progressive right side hemiatrophy. The patient has resistant epilepsy, left side hemiparesis, and good language and cognitive development. Conclusion. Despite IHHE described many years ago, some syndrome?s features, including etiology, have remained unexplained. The association between IHHE and GRIN2A mutation stated in the current manuscript is described in scientific literature for the first time.

A case with GRIN2A mutation and its non-neurological manifestations

A case with <i>GRIN2A</i> mutation and its non-neurological manifestations

Gene Therapy Repairs for the Epileptic Brain: Potential for Treatment and Future Directions.

Epilepsy is a syndrome specified by frequent seizures and is one of the most prevalent neurological conditions, and that one-third of people of epilepsy are resistant to available drugs. Surgery is supposed to be the main treatment for the remedy of multiple drug-resistant epilepsy, but it is a drastic procedure. Advancement in genomic technologies indicates that gene therapy can make such surgery unnecessary. The considerable number of new studies show the significance of mutation in mammalian target of rapamycin pathway, NMDA receptors, GABA receptors, potassium channels and G-protein coupled receptors. Illustration of the meticulous drug in epilepsy targeting new expression of mutations in SCN8A, GRIN2A, GRIN2D and KCNT1 are conferred. Various methods are utilized to express a gene in a precise area of the brain; Transplantation of cells in an ex vivo approach (fetal cells, fibroblasts, immortalized cells), nonviral vector delivery and viral vector delivery like retrovirus, herpes simplex virus adenovirus and adeno-related virus. Gene therapy has thus been explored to generate anti-epileptogenic, anti-seizure and disease-modifying effects. Specific targeting of the epileptogenic region is facilitated by gene therapy, hence sparing the adjacent healthy tissue and decreasing the adverse effects that frequently go hand in hand with antiepileptic medication.