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Aim Methods Results Conclusion Whole‐exome sequencing (WES) studies have revealed that germline de novo variants (gDNVs) contribute to the genetic etiology of schizophrenia. However, the contribution of mosaic DNVs (mDNVs) to the risk of schizophrenia remains to be elucidated. In the present study, we systematically investigated the gDNVs and mDMVs that contribute to the genetic etiology of schizophrenia in a Japanese population.We performed deep WES (depth: 460×) of 73 affected offspring and WES (depth: 116×) of 134 parents from 67 families with schizophrenia. Prioritized rare nonsynonymous gDNV and mDNV candidates were validated using Sanger sequencing and ultra‐deep targeted amplicon sequencing (depth: 71,375×), respectively. Subsequently, we performed a Gene Ontology analysis of the gDNVs and mDNVs to obtain biological insights. Lastly, we selected DNVs in known risk genes for psychiatric and neurodevelopmental disorders.We identified 62 gDNVs and 98 mDNVs. The Gene Ontology analysis of mDNVs implicated actin filament and actin cytoskeleton as candidate biological pathways. There were eight DNVs in known risk genes: splice region gDNVs in AKAP11 and CUL1; a frameshift gDNV in SHANK1; a missense gDNV in SRCAP; missense mDNVs in CTNNB1, GRIN2A, and TSC2; and a nonsense mDNV in ZFHX4.Our results suggest the potential contributions of rare nonsynonymous gDNVs and mDNVs to the genetic etiology of schizophrenia. This is the first report of the mDNVs in schizophrenia trios, demonstrating their potential relevance to schizophrenia pathology. [ABSTRACT FROM AUTHOR]

Background: Spitz 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 presentation: Here, 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. Conclusion: This case introduces a novel fusion partner of MAP3K8 in the context of Spitz melanoma and expands the morphologic and molecular spectrum of Spitz melanoma. [ABSTRACT FROM AUTHOR]

Abstract Background Spitz 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 presentation Here, 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. Conclusion This case introduces a novel fusion partner of MAP3K8 in the context of Spitz melanoma and expands the morphologic and molecular spectrum of Spitz melanoma.

• Variants in DEPDC5, SCN1A, PCDH19 and GRIN2A are a frequent finding in patients with focal epilepsy. • SCN1A and PCDH19 gene null variants can be found in patients with focal epilepsy and normal intellectual function. • Targeted genetic sequencing with small tailored gene panels could be a viable diagnostic option for epilepsy centers with limited resources. Next generation sequencing (NGS) has greatly expanded our understanding of genetic contributors in multiple epilepsy syndromes, including focal epilepsy. Describing the genetic architecture of common syndromes promises to facilitate the diagnostic process as well as aid in the identification of patients who stand to benefit from genetic testing, but most studies to date have been limited to examining children or adults with intellectual disability. Our aim was to determine the yield of targeted sequencing of 5 established epilepsy genes (DEPDC5, LGI1, SCN1A, GRIN2A, and PCHD19) in an extensively phenotyped cohort of focal epilepsy patients with normal intellectual function or mild intellectual disability, as well as describe novel variants and determine the characteristics of variant carriers. Targeted panel sequencing was performed on 96 patients with a strong clinical suspicion of genetic focal epilepsy. Patients had previously gone through a comprehensive diagnostic epilepsy evaluation in The Neurology Clinic, University Clinical Center of Serbia. Variants of interest (VOI) were classified using the American College of Medical Genetics and the Association for Molecular Pathology criteria. Six VOI in eight (8/96, 8.3%) patients were found in our cohort. Four likely pathogenic VOI were determined in six (6/96, 6.2%) patients, two DEPDC5 variants in two patients, one SCN1A variant in two patients and one PCDH19 variant in two patients. One variant of unknown significance (VUS) was found in GRIN2A in one (1/96, 1.0%) patient. Only one VOI in GRIN2A was classified as likely benign. No VOI were detected in LGI1. Sequencing of only five known epilepsy genes yielded a diagnostic result in 6.2% of our cohort and revealed multiple novel variants. Further research is necessary for a better understanding of the genetic basis in common epilepsy syndromes in patients with normal intellectual function or mild intellectual disability. [ABSTRACT FROM AUTHOR]

Background: Personal variations in genetic risk for schizophrenia relate to its phenotypic heterogeneity—both in disorder development and clinical manifestations. Abnormal glutamatergic neurotransmitter system functioning is integrated in the pathogenesis of schizophrenia. Methods: A sample of 805 Russian schizophrenia patients from the Siberian Federal region was investigated. We examined the association of 39 single nucleotide polymorphisms in eight genes (GRIN2A, GRIN2B, SLC1A2, SLC1A3, SLC17A7, GRM3, GRM7, and GRM8) involved in the glutamatergic system with the development of clinical heterogeneity of schizophrenia. The MassARRAY Analyzer 4 was used for genotyping. Results: GRIN2A rs11644461, rs8057394 and GRIN2B rs7313149 are associated with the continuous type of schizophrenia. The GRIN2A rs8057394*G allele is a relative risk factor (p = 0.019) for developing the continuous type of schizophrenia. We found a nominally significant association between negative symptoms of schizophrenia and SLC17A7 rs62126236. The SLC17A7 rs62126236*T allele has a protective effect (p = 0.039) against predominant negative symptoms in schizophrenia. The total Positive and Negative Syndrome Scale (PANSS) scores were significantly associated with GRIN2A rs9788936 after adjusting for multiple testing (p = 0.001). Conclusions: In this study the contribution of the glutamatergic gene polymorphisms to the clinical heterogeneity of schizophrenia has been demonstrated. [ABSTRACT FROM AUTHOR]

Abstract Background Alternating of Childhood (AHC) is an uncommon and complex disorder characterized by age of onset before 18 months with recurrent hemiplegia of one or either sides of the body or quadriplegia. The disorder is mainly caused by mutations in ATP1A3 gene, and to a lesser extent in ATP1A2 gene. In AHC neurological co-morbidities are various and frequently reported including developmental delay, epilepsy, tonic or dystonic spells, nystagmus,autonomic manifestations with intrafamilial variability. Case presentation Clinical and genetic findings of a couple of twins (Family 1: Case 1 and Case 2) and a couple of siblings (Family 2: Case 3 and Case 4) coming from two different Italian families affected by AHC were deeply examined. In twins of Family 1, a pathogenic variant in ATP1A3 gene (c.2318A>G) was detected. In siblings of Family 2, the younger brother showed a novel GRIN2A variant (c.3175 T > A), while the older carried the same GRIN2A variant, and two missense mutations in SCNIB (c.632 > A) and KCNQ2 (1870 G > A) genes. Clinical manifestations of the four affected children were reported along with cases of AHC drawn from the literature. Conclusions Hemiplegic episode is only a sign even if the most remarkable of several and various neurological comorbidities in AHC affected individuals. Molecular analysis of the families here reported showed that clinical features of AHC may be also the result of an unexpected genetic heterogeneity.

IntroductionWomen have a shorter course from initial cocaine use to meeting the criteria for cocaine use disorder as compared to men. Preclinical findings similarly indicate that females develop key features of an addiction-like phenotype faster than males, including an enhanced motivation for cocaine and compulsive use, indicating that this phenomenon is biologically based. The goals of this study were to determine whether cocaine-craving, another key feature of addiction, also develops sooner during withdrawal in females than males and to determine whether there are sex differences in the molecular mechanisms associated with its development focusing on markers known to mediate cocaine-craving in males (i.e., dorsomedial prefrontal cortex, dmPFC, expression of brain-derived neurotrophic factor exon-IV, Bdnf-IV, and NMDA receptor subunits, Grin2a, Grin2b, and Grin1).MethodsCocaine-craving was assessed following extended-access cocaine self-administration and 2, 7, or 14 days of withdrawal using an extinction/cue-induced reinstatement procedure. Tissue was obtained from the dmPFC immediately after reinstatement testing and gene expression changes were analyzed using real-time qPCR.ResultsIn males, cocaine-craving (total extinction and cue-induced reinstatement responding) progressively increased from early to later withdrawal time-points whereas in females, cocaine-craving was already elevated during early withdrawal (after 2 days) and did not further increase at later withdrawal time-points. Levels of cocaine-craving, however, were similar between the sexes. Gene expression changes differed markedly between the sexes such that males showed the expected relapse- and withdrawal-associated changes in Bdnf-IV, Grin2a, Grin2b, and Grin1 expression, but females only showed a modest increase Grin1 expression at the intermediate withdrawal timepoint.DiscussionThese findings indicate that cocaine-craving is similarly expressed in males and females although the time-course for its incubation appears to be accelerated in females; the molecular mechanisms also likely differ in females versus males.

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Caffeine is neuroprotective in animal models of Parkinson's disease (PD) and caffeine intake is inversely associated with the risk of PD. This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p=0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD.

Purpose: Previous studies have found the neurodegeneration and atrophy of glaucomatous lateral geniculate nucleus (LGN), but the mechanism is still unknown. Circular RNA (circRNA) plays some important roles in physiological and pathological progression of the disease. In this study, we focused on the differentially expressed circRNAs and the mechanism for circXPO5 in LGN degeneration in a macaque glaucoma model. Methods: Using RNA-seq, we analyzed the differentially expressed circRNAs in a macaque glaucoma model. An RT-QPCR was used to check the expression of selected differentially expressed circRNAs, candidate miRNAs and mRNAs. A competing endogenous RNA (ceRNA) network analysis was performed to examine the mechanism of circXPO5 action. Results: circXPO5 significantly decreased in the glaucoma model and a ceRNA network analysis revealed that circXPO5 can bind to miR-330-5p, which also binds to GRIN2A (ionotropic receptor NMDA type subunit 2A). QPCR detection showed a decrease in GRIN2A and an increase in miR-330-5p. Conclusions: Our earlier studies revealed that the GRIN2A gene regulates the calcium signal pathway. Decreasing of GRIN2A related with neuron apoptosis and neurodegeneration. These findings indicate that the reduction in circXPO5 may have a protective effect on neuronal apoptosis in the visual central system of glaucoma. [ABSTRACT FROM AUTHOR]

Introduction. Infantile hemiconvulsion–hemiplegia and epilepsy (IHHE) syndrome is defined as a specific syndrome in patients < 2 years of age, presenting as a new onset refractory status epilepticus with unilateral motor seizures and acute imaging abnormalities, fever, hemiparesis > 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.

Background: Alternating of Childhood (AHC) is an uncommon and complex disorder characterized by age of onset before 18 months with recurrent hemiplegia of one or either sides of the body or quadriplegia. The disorder is mainly caused by mutations in ATP1A3 gene, and to a lesser extent in ATP1A2 gene. In AHC neurological co-morbidities are various and frequently reported including developmental delay, epilepsy, tonic or dystonic spells, nystagmus,autonomic manifestations with intrafamilial variability. Case presentation: Clinical and genetic findings of a couple of twins (Family 1: Case 1 and Case 2) and a couple of siblings (Family 2: Case 3 and Case 4) coming from two different Italian families affected by AHC were deeply examined. In twins of Family 1, a pathogenic variant in ATP1A3 gene (c.2318A>G) was detected. In siblings of Family 2, the younger brother showed a novel GRIN2A variant (c.3175 T > A), while the older carried the same GRIN2A variant, and two missense mutations in SCNIB (c.632 > A) and KCNQ2 (1870 G > A) genes. Clinical manifestations of the four affected children were reported along with cases of AHC drawn from the literature. Conclusions: Hemiplegic episode is only a sign even if the most remarkable of several and various neurological comorbidities in AHC affected individuals. Molecular analysis of the families here reported showed that clinical features of AHC may be also the result of an unexpected genetic heterogeneity. [ABSTRACT FROM AUTHOR]

We report a 2.5-year-old Turkish boy who first presented with nystagmus, lack of eye contact, and hypotonia at 2 months of age and developed refractory seizures when 6 months old. Extensive metabolic tests and imaging being noncontributory, whole-exome sequencing was carried out which revealed a heterozygote NM_001134407.2:C.3299A>G (p.Glu1100Gly) novel mutation in GRIN2A gene. Topiramate was started and seizures were rapidly brought under control. GRIN2A mutations may result in altered GluN2A membrane trafficking and response to glutamate. This report illustrates the clinical variability of GRIN2A mutations according to the age of onset of symptoms and suggests considering mutations in this gene in cases of global developmental delay, refractory epilepsy, and nystagmus.

Memantine is an N-methyl-D-aspartate receptor (NMDA-R) antagonist, approved for dementia, but also studied in pediatric autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). We reviewed children treated with memantine in a single-centre pediatric neurology clinic. Clinical data extracted included age, sex, weight, clinical history, reason for memantine prescription, period of treatment trial and dosage, treatment response, side effects, and concomitant medications. Eight patients met inclusion criteria with diagnoses including developmental and epileptic encephalopathy, focal epilepsy, ASD, ADHD. Four reported clear cognitive improvement, though two of these started other concurrent treatments at the time of memantine initiation. One of three patients with poorly-controlled epilepsy, a girl with a GRIN2A variant of uncertain significance, had a clear reduction in seizure frequency. No serious adverse events were noted. Memantine is generally well-tolerated in children, and may have potential benefit for a broad range of pediatric neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

• We identified eight brain-region-specific coexpression subnetworks associated with cigarettes per day, all of which were critical to the neural process of substance misuse, implicating the neurogenetic mechanisms of individual variation in nicotine use severity. • The three brain region-specific hub proteins, GRIN2A, PMCA2, and SV2B, are encoded by genes implicated in stress response, drug memory, calcium homeostasis, and inhibitory control. • All significant protein interaction subnetworks showed involvement in the pancreatic secretion pathway, indicating a pleiotropic connection between cigarette smoking and pancreatic diseases. Our study focused on human brain transcriptomes and the genetic risks of cigarettes per day (CPD) to investigate the neurogenetic mechanisms of individual variation in nicotine use severity. We constructed whole-brain and intramodular region-specific coexpression networks using BrainSpan's transcriptomes, and the genomewide association studies identified risk variants of CPD, confirmed the associations between CPD and each gene set in the region-specific subnetworks using an independent dataset, and conducted bioinformatic analyses. Eight brain-region-specific coexpression subnetworks were identified in association with CPD: amygdala, hippocampus, medial prefrontal cortex (MPFC), orbitofrontal cortex (OPFC), dorsolateral prefrontal cortex, striatum, mediodorsal nucleus of the thalamus (MDTHAL), and primary motor cortex (M1C). Each gene set in the eight subnetworks was associated with CPD. We also identified three hub proteins encoded by GRIN2A in the amygdala, PMCA2 in the hippocampus, MPFC, OPFC, striatum, and MDTHAL, and SV2B in M1C. Intriguingly, the pancreatic secretion pathway appeared in all the significant protein interaction subnetworks, suggesting pleiotropic effects between cigarette smoking and pancreatic diseases. The three hub proteins and genes are implicated in stress response, drug memory, calcium homeostasis, and inhibitory control. These findings provide novel evidence of the neurogenetic underpinnings of smoking severity. [ABSTRACT FROM AUTHOR]

Purpose: Previous studies have found the neurodegeneration and atrophy of glaucomatous lateral geniculate nucleus (LGN), but the mechanism is still unknown. Circular RNA (circRNA) plays some important roles in physiological and pathological progression of the disease. In this study, we focused on the differentially expressed circRNAs and the mechanism for circXPO5 in LGN degeneration in a macaque glaucoma model. Methods: Using RNA-seq, we analyzed the differentially expressed circRNAs in a macaque glaucoma model. An RT-QPCR was used to check the expression of selected differentially expressed circRNAs, candidate miRNAs and mRNAs. A competing endogenous RNA (ceRNA) network analysis was performed to examine the mechanism of circXPO5 action. Results: circXPO5 significantly decreased in the glaucoma model and a ceRNA network analysis revealed that circXPO5 can bind to miR-330-5p, which also binds to GRIN2A (ionotropic receptor NMDA type subunit 2A). QPCR detection showed a decrease in GRIN2A and an increase in miR-330-5p. Conclusions: Our earlier studies revealed that the GRIN2A gene regulates the calcium signal pathway. Decreasing of GRIN2A related with neuron apoptosis and neurodegeneration. These findings indicate that the reduction in circXPO5 may have a protective effect on neuronal apoptosis in the visual central system of glaucoma.

NMDA receptors (NMDARs) are glutamate‐gated ion channels that contribute to nearly all brain processes. Not surprisingly then, genetic variations in the genes encoding NMDAR subunits can be associated with neurodevelopmental, neurological and psychiatric disorders. These disease‐associated variants (DAVs) present challenges, such as defining how DAV‐induced alterations in receptor function contribute to disease progression and how to treat the affected individual clinically. As a starting point to overcome these challenges, we need to refine our understanding of the complexity of NMDAR structure function. In this regard, DAVs have expanded our knowledge of NMDARs because they do not just target well‐known structure‐function motifs, but rather give an unbiased view of structural elements that are important to the biology of NMDARs. Indeed, established NMDAR structure‐function motifs have been validated by the appearance of disorders in patients where these motifs have been altered, and DAVs have identified novel structural features in NMDARs such as gating triads and hinges in the gating machinery. Still, the majority of DAVs remain unexplored and occur at sites in the protein with unidentified function or alter receptor properties in multiple and unanticipated ways. Detailed mechanistic and structural investigations are required of both established and novel motifs to develop a highly refined pathomechanistic model that accounts for the complex machinery that regulates NMDARs. Such a model would provide a template for rational drug design and a starting point for personalized medicine. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the correlation between GRIN2A rs387906637 polymorphism and susceptibility to epilepsy. Blood samples were collected from 85 volunteers, dividing into 60 epilepsy patients (34 males and 26 females) and 25 healthy subjects (19 males and 6 females).The DNA was extracted and GRIN2A rs387906637 polymorphism was analyzed by Real-time PCR using two probes and primers. The results showed no significant differences between patients and control samples; therefore, there are no allelic and genotypic correlations of this SNP with epilepsy. This study indicated that GRIN2A rs387906637 polymorphism is not a risk factor for epilepsy in the studied set of patients. [ABSTRACT FROM AUTHOR]

We report a 2.5-year-old Turkish boy who first presented with nystagmus, lack of eye contact, and hypotonia at 2 months of age and developed refractory seizures when 6 months old. Extensive metabolic tests and imaging being noncontributory, whole-exome sequencing was carried out which revealed a heterozygote NM_001134407.2:C.3299A>G (p.Glu1100Gly) novel mutation in GRIN2A gene. Topiramate was started and seizures were rapidly brought under control. GRIN2A mutations may result in altered GluN2A membrane trafficking and response to glutamate. This report illustrates the clinical variability of GRIN2A mutations according to the age of onset of symptoms and suggests considering mutations in this gene in cases of global developmental delay, refractory epilepsy, and nystagmus. [ABSTRACT FROM AUTHOR]

Rapid advances in sequencing technology have led to an explosive increase in the number of genetic variants identified in patients with neurological disease and have also enabled the assembly of a robust database of variants in healthy individuals. A surprising number of variants in the GRIN genes that encode N-methyl-D-aspartate (NMDA) glutamatergic receptor subunits have been found in patients with various neuropsychiatric disorders, including autism spectrum disorders, epilepsy, intellectual disability, attention-deficit/hyperactivity disorder, and schizophrenia. This review compares and contrasts the available information describing the clinical and functional consequences of genetic variations in GRIN2A and GRIN2B. Comparison of clinical phenotypes shows that GRIN2A variants are commonly associated with an epileptic phenotype but that GRIN2B variants are commonly found in patients with neurodevelopmental disorders. These observations emphasize the distinct roles that the gene products serve in circuit function and suggest that functional analysis of GRIN2A and GRIN2B variation may provide insight into the molecular mechanisms, which will allow more accurate subclassification of clinical phenotypes. Furthermore, characterization of the pharmacological properties of variant receptors could provide the first opportunity for translational therapeutic strategies for these GRIN-related neurological and psychiatric disorders.

Background: Schizophrenia is a complex mental disorder with a high heritability. Dysfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptors may be involved in the pathogenesis of schizophrenia. In this study, we examined the contribution of GRIN2A and GRIN2B (Glutamate Ionotropic Receptor NMDA Type Subunit 2A/2B) polymorphisms to the clinical features of schizophrenia, such as the leading symptoms, the type of course, and the age of onset. Methods: A population of 402 Russian patients with schizophrenia from the Siberian region was investigated. Genotyping of seventeen single-nucleotide polymorphisms (SNPs) in GRIN2A and GRIN2B was performed using QuantStudio™ 3D Digital PCR System Life Technologies amplifier using TaqMan Validated SNP Genotyping Assay kits (Applied Biosystems). The results were analyzed using Chi-square and the Fisher’s exact tests. Results: We found an association of GRIN2A rs7206256 and rs11644461 and GRIN2B rs7313149 with the early onset (before the age of 18 years old) schizophrenia. We did not reveal any associations of GRIN2A and GRIN2B polymorphisms with leading (positive vs. negative) symptoms or type of course (continuous vs. episodic) of schizophrenia. Conclusions: In the study, we confirmed the involvement of the GRIN2A and GRIN2B genes in the early onset of schizophrenia in a Russian population of the Siberian region.

Purpose: Chromosome 3 loss is an independent risk factor for uveal melanoma (UM), but its exact molecular mechanisms remain unclear. This study was designed to investigate the relationship between chromosome 3 loss and molecular alterations at multiple levels to construct a prognostic model., Methods: Forty-four UM cases with chromosome 3 loss (chr3 del group) and 36 UM cases without copy number variation on chromosome 3 (chr3 wt group) were collected from the Cancer Genome Atlas (TCGA). The TCGA dataset was subjected to a univariate Cox regression analysis to identify different expressed genes, and a subsequent random forest algorithm analysis revealed significant changes in different expressed genes, which were used to develop key biomarkers for UM. Following that, the immune cell infiltration analysis and drug sensitivity analyses were carried out. The UM cell line was then utilized to investigate the potential functions of the key biomarker via cell apoptosis, proliferation, cycle assays, WB, and RT-qPCR., Results: By analyzing the 80 cases data in TCGA, the authors unveiled molecular changes relevant to loss of chromosome 3 in UM as well as their poor survival. In addition, machine learning analysis identified three hub genes (GRIN2A, ACAN, and MMP9) as potential therapeutic targets. The differentially enriched pathways between the two groups were mainly about immune-system activity, and hub genes expression was also highly correlated with immune infiltration levels., Conclusion: Chromosome 3 loss has considerable clinical significance for UM, and GRIN2A may be useful in diagnosing, treating, and prognosticating the condition., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Glutamate‐gated N‐methyl‐d‐aspartate receptors (NMDARs) are instrumental to brain development and functioning. Defects in the GRIN2A gene, encoding the GluN2A subunit of NMDARs, cause slow‐wave sleep (SWS)‐related disorders of the epilepsy‐aphasia spectrum (EAS). The as‐yet poorly understood developmental sequence of early EAS‐related phenotypes, and the role of GluN2A‐containing NMDARs in the development of SWS and associated electroencephalographic (EEG) activity patterns, were investigated in Grin2a knockout (KO) mice. Methods: Early social communication was investigated by ultrasonic vocalization (USV) recordings; the relationship of electrical activity of the cerebral cortex with SWS was studied using deep local field potential or chronic EEG recordings at various postnatal stages. Results: Grin2a KO pups displayed altered USV and increased occurrence of high‐voltage spindles. The pattern of slow‐wave activity induced by low‐dose isoflurane was altered in Grin2a KO mice in the 3rd postnatal week and at 1 month of age. These alterations included strong suppression of the delta oscillation power and an increase in the occurrence of the spike‐wave bursts. The proportion of SWS and the sleep quality were transiently reduced in Grin2a KO mice aged 1 month but recovered by the age of 2 months. Grin2a KO mice also displayed spontaneous spike‐wave discharges, which occurred nearly exclusively during SWS, at 1 and 2 months of age. Significance: The impaired vocal communication, the spike‐wave discharges occurring almost exclusively in SWS, and the age‐dependent alteration of SWS that were all seen in Grin2a KO mice matched the sleep‐related and age‐dependent manifestations seen in children with EAS, hence validating the Grin2a KO as a reliable model of EAS disorders. Our data also show that GluN2A‐containing NMDARs are involved in slow‐wave activity, and that the period of postnatal brain development (postnatal day 30) when several anomalies peaked might be critical for GluN2A‐dependent, sleep‐related physiological and pathological processes. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Several lines of evidence support the hypothesis that impaired functioning of the glutamatergic N -methyl- d -aspartate receptor (NMDAR) might be involved in the etiology of schizophrenia. NMDAR is activated by phosphorylation by Fyn, and there is also some evidence to suggest that abnormalities in Fyn functionality could also be involved in susceptibility to schizophrenia. In a recent weighted burden analysis of exome-sequenced schizophrenia cases and controls, we noted modest statistical evidence for an enrichment of rare, functional variants in FYN , GRIN1 , and GRIN2B in schizophrenia cases. Aim: To test the plausibility of the hypothesis that schizophrenia susceptibility might be associated with genetic variants predicted to cause impaired functioning of NMDAR, either directly or indirectly through impairment of the kinases that phosphorylate it. Methods: In an exome-sequenced sample of 4225 schizophrenia cases and 5834 controls, rare variants occurring in genes for the NMDAR subunits and for the kinases acting on it were annotated. The counts of disruptive and damaging variants were compared between cases and controls, and the distribution of amino acids affected by damaging variants was visualised in ProteinPaint and the RCSB Protein Data Bank. Special attention was paid to tyrosine residues subject to phosphorylation. Results: There was no suggestion that abnormalities of the serine–threonine kinases or of Src were associated with schizophrenia. Overall, three cases and no controls had a disruptive variant in GRIN2A and two cases and no controls had a disruptive variant in FYN. Moreover, 14 cases and three controls had damaging variants in FYN , and all the variants in controls affected amino acid residues in the N-terminal region outside of any known functional domains. By contrast, 10 variants in cases affected amino acids in functional domains, and in the 3D structure of Fyn, two of the amino acid substitutions, A376T and Q517E, were adjacent to each other. A total of eight cases and one control had damaging variants in GRIN1 , but there was no obvious pattern with respect to particular functional domains being affected in this or other genes. A single case had a variant in GRIN2A affecting a well-supported phosphorylation site, Y943C, and three cases had a variant in FYN which produces an amino acid change, T216S, which lies two residues away from two adjacent well-supported phosphorylation sites. Aside from this, there was no suggestion that tyrosine phosphorylation sites in Fyn or NMDAR were affected. Conclusion: The numbers of variants involved are too small for firm conclusions to be drawn. The results are consistent with the hypothesis that ∼0.5% of patients with schizophrenia have disruptive or damaging genetic variants, which could plausibly impair functioning of NMDAR directly or indirectly through impairing Fyn function. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Mice lacking Grin2a , a human risk gene, model several aspects of schizophrenia • Grin2a +/− mice show prefrontal cortex hypoactivity and hippocampal hyperactivity • Hyperdopaminergic state in striatum and amphetamine hypersensitivity in Grin2a +/− mice • Astrocytes, oligodendrocytes, and diverse neuronal types are affected in Grin2a +/− mice Farsi et al. show that heterozygous mouse mutants of Grin2a , a human schizophrenia risk gene, display major changes at the transcriptomic, proteomic, behavioral, and neurophysiological levels, affecting widespread brain regions, diverse cell types, and multiple signaling pathways, with several abnormal features that resemble schizophrenia patients. [ABSTRACT FROM AUTHOR]

Evidences have indicated a high degree of comorbidity of alcoholism and depression. N-acetylcysteine (NAC) has shown its clinical efficiency in the treatment of several psychiatric disorders and is identified as a multi-target acting drug. The ability of NAC to prevent alcohol abstinence-induced depression-like effects and underlying mechanism(s) have not been adequately addressed. This study was aimed to investigate the beneficial effects of NAC in the alcohol abstinence-induced depression developed following long-term voluntary alcohol intake. For evaluation of the effects of NAC, Sprague–Dawley rats were enabled to voluntary drinking of 4.5%, 7.5% and 9% v/v alcohol for fifteen days. NAC (25, 50, and 100 mg/kg) and fluoxetine (5 mg/kg) were injected intraperitoneally for three consecutive days during the alcohol abstinence period on the days 16, 17, 18. The behavioral studies were conducted employing forced swim test (FST), and tail suspension test (TST) on day 18 to determine the effects of N-acetylcysteine and fluoxetine in the ethanol withdrawal induced-depression. Blood alcohol concentration, alcohol biomarkers like SGPT, SGOT, ALP, GGT, and MCV were estimated by using commercially available kits. Serotonin concentrations were measured in the plasma, hippocampus and pre-frontal cortex using the rat ELISA kit. The expression of GRIN1 , GRIN2A , GRIN2B genes for the N-methyl d -aspartate receptors (NMDAR) subunits in the hippocampus and the prefrontal cortex were also examined by reverse-transcription quantitative polymerase chain reaction. The results revealed that alcohol abstinence group depicted increased immobility time in FST and TST. Further, NAC exerted significant protective effect at the doses 50 mg/kg and 100 mg/kg, but 25 mg/kg showed insignificant protection against alcohol abstinence-induced depression. The increased level of biochemical parameters following ethanol abstinence were also reversed by NAC at the dose of 100 mg/kg. The significant reversal effect of NAC on the serotonin level following alcohol abstinence was greater in the hippocampus as compared to the third-day alcohol withdrawal group. The increased expression levels of GRIN2A and GRIN2B following ethanol abstinence were reversed with a higher dose of NAC (100 mg/kg) treatment. In conclusion, the results of the study reveal that NAC has remarkable protective effects in the alcohol abstinence-induced depression by modulating alcohol markers, serotonin levels and GRIN2A , GRIN2B gene expression of NMDAR signaling pathway in rats. [ABSTRACT FROM AUTHOR]

Drug dependence is a chronic brain disease with harmful consequences for both individual users and society. Glutamate is a primary excitatory neurotransmitter in the brain, and both in vivo and in vitro experiments have implicated N-methyl-D-aspartate (NMDA) receptor, a glutamate receptor, as an element in various types of addiction. Recent findings from genetics-based approaches such as genome-wide linkage, candidate gene association, genome-wide association (GWA), and next-generation sequencing have demonstrated the significant association of NMDA receptor subunit genes such as GluN3A, GluN2B, and GluN2A with various addiction-related phenotypes. Of these genes, GluN3A has been the most studied, and it has been revealed to play crucial roles in the etiology of addictions. In this communication, we provide an updated view of the genetic effects of NMDA receptor subunit genes and their functions in the etiology of addictions based on the findings from investigation of both common and rare variants as well as SNP-SNP interactions. To better understand the molecular mechanisms underlying addiction-related behaviors and to promote the development of specific medicines for the prevention and treatment of addictions, current efforts aim not only to identify more causal variants in NMDA receptor subunits by using large independent samples but also to reveal the molecular functions of these variants in addictions. [ABSTRACT FROM AUTHOR]

Common alleles associated with psychiatric disorders are often regarded as deleterious genes that influence vulnerability to disease, but they may also be considered as mediators of variation in adaptively structured cognitive phenotypes among healthy individuals. The schizophrenia-associated gene GRIN2A (glutamate ionotropic receptor NMDA type subunit 2a) codes for a protein subunit of the NMDA (N-methyl-D-aspartate) receptor that underlies central aspects of human cognition. Pharmacological NMDA blockage recapitulates the major features of schizophrenia in human subjects, and represents a key model for the neurological basis of this disorder. We genotyped two functional GRIN2A polymorphisms in a large population of healthy individuals who were scored for schizotypy and mental imagery/manipulation (the mental rotation test). Rare-allele homozygosity of the promoter microsatellite rs3219790 was associated with high total schizotypy (after adjustment for multiple comparisons) and with enhanced mental rotation ability (nominally, but not after adjustment for multiple comparisons), among males. These findings provide preliminary evidence regarding a genetic basis to previous reports of enhanced mental imagery in schizophrenia and schizotypy. The results also suggest that some schizophrenia-related alleles may be subject to cognitive tradeoffs involving both positive and negative effects on psychological phenotypes, which may help to explain the maintenance of psychiatric-disorder risk alleles in human populations. [ABSTRACT FROM AUTHOR]

Background: Mutations in the GRIN2A gene, which encodes the GluN2A (glutamate [NMDA] receptor subunit epsilon-1) subunit of the N-methyl-d-aspartate receptor, have been identified in patients with epilepsy-aphasia spectrum disorders, idiopathic focal epilepsies with centrotemporal spikes, and epileptic encephalopathies with severe developmental delay. However, thus far, mutations in this gene have not been associated with a nonepileptic neurodevelopmental disorder with dystonia.Objectives: The objective of this study was to identify the disease-causing gene in 2 siblings with neurodevelopmental and movement disorders with no epileptiform abnormalities.Methods: The study method was targeted next-generation sequencing panel for neuropediatric disorders and subsequent electrophysiological studies.Results: The 2 siblings carry a novel missense mutation in the GRIN2A gene (p.Ala643Asp) that was not detected in genomic DNA isolated from blood cells of their parents, suggesting that the mutation is the consequence of germinal mosaicism in 1 progenitor. In functional studies, the GluN2A-A643D mutation increased the potency of the agonists L-glutamate and glycine and decreased the potency of endogenous negative modulators, including protons, magnesium and zinc but reduced agonist-evoked peak current response in mammalian cells, suggesting that this mutation has a mixed effect on N-methyl-d-aspartate receptor function.Conclusion: De novo GRIN2A mutations can give rise to a neurodevelopmental and movement disorder without epilepsy. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Caffeine intake has been inversely associated with Parkinson's disease (PD) risk. This relationship may be modified by polymorphisms of glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) and cytochrome P450 1A2 (CYP1A2), but the results of previous studies have been inconsistent.Method: We examined the interaction of caffeine intake with GRIN2A-rs4998386 and CYP1A2-rs762551 polymorphisms in influencing PD risk among 829 incident cases of PD and 2,754 matched controls selected among participants in the following 3 large prospective ongoing cohorts: the Nurses' Health Study, the Health Professionals' Follow-up Study, and the Cancer Prevention Study II Nutrition Cohort. Matching factors included cohort, birth year, source of DNA, date of DNA collection, and race. Relative risks and 95% confidence intervals were estimated using conditional logistic models. Interactions were tested both on the multiplicative scale and on the additive scale.Results: Overall, caffeine intake was associated with a lower PD risk (adjusted relative risk for highest versus lowest tertile = 0.70; 95% confidence interval, 0.57-0.86; p < .001). In analyses stratified by the GRIN2A-rs4998386 genotype, the multivariable-adjusted relative risk of PD comparing the highest to the lowest tertile of caffeine was 0.69 (95% confidence interval, 0.55-0.88; p < .01) among individuals homozygous for the C allele, and 0.85 (95% confidence interval, 0.55-1.32; p = .47; pRERI  = .43) among carriers for the T allele. Interactions between caffeine and GRIN2A were not significant in either the multiplicative or additive scales. We also did not observe significant interactions for CYP1A2-rs762551 and incident PD risk.Conclusion: Our findings do not support the hypothesis of an interaction between the GRIN2A-rs4998386 or CYP1A2-rs762551 polymorphism and caffeine intake in determining PD risk. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objective Epilepsy-aphasia spectrum (EAS) are a group of epilepsy syndromes denoting an association between epilepsy, speech disorders and the EEG signature of centrotemporal spikes. Mutations in the GRIN2A gene, encoding the NMDA glutamate receptor α2 subunit were reported in focal epilepsy with speech disorder. We aimed to explore the role of GRIN2A mutations in patients with centrotemporal spikes related epileptic syndromes in a Chinese cohort. Methods Patients with Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), atypical benign partial epilepsy (ABPE), and benign epilepsy with centrotemporal spikes (BECTS) were recruited. GRIN2A mutation screening was performed using PCR and Sanger sequencing. Results 122 patients, including 9 LKS, 26 ECSWS, 42 ABPE and 45 BECTS were enrolled. The mean age of seizure or aphasia onset was 5 years, ranging from 10 months to 11 years. Heterozygous GRIN2A mutations were detected in four patients (G760S, D1385Y, C455Y and C231R) GRIN2A mutation was found in 11.1% (1 out of 9 cases) of LKS, and in 7.1% (3 out of 42 cases) of ABPE, but in none with ECSWS and BECTS. No GRIN2A mutation was found in patients with a family history of febrile seizures or epilepsy. Conclusion GRIN2A mutation is a genetic cause in less than 11% patients with LKS or ABPE. GRIN2A gene is a rare causative gene in Chinese patients with EAS, suggesting the possibility of other gene involved in the pathogenesis. [ABSTRACT FROM AUTHOR]

Genetic variants of the glutamate activated N-methyl-D-aspartate (NMDA) receptor (NMDAR) subunit GluN2A are associated with the hyperexcitable states manifested by epileptic seizures and interictal discharges in patients with disorders of the epilepsy-aphasia spectrum (EAS). The variants found in sporadic cases and families are of different types and include microdeletions encompassing the corresponding GRIN2A gene as well as nonsense, splice-site and missense GRIN2A defects. They are located at different functional domains of GluN2A and no clear genotype-phenotype correlation has emerged yet. Moreover, GluN2A variants may be associated with phenotypic pleiotropy. Deciphering the consequences of pathogenic GRIN2A variants would surely help in better understanding of the underlying mechanisms. This emphasizes the need for functional studies to unravel the basic functional properties of each specific NMDAR variant. In the present study, we have used patch-clamp recordings to evaluate kinetic changes of mutant NMDARs reconstituted after co-transfection of cultured cells with the appropriate expression vectors. Three previously identified missense variants found in patients or families with disorders of the EAS and situated in the N-terminal domain (p.Ile184Ser) or in the ligand-binding domain (p.Arg518His and p.Ala716Thr) of GluN2A were studied in both the homozygous and heterozygous conditions. Relative surface expression and current amplitude were significantly reduced for NMDARs composed of mutant p.Ile184Ser and p.Arg518His, but not p.Ala716His, as compared with wild-type (WT) NMDARs. Amplitude of whole-cell currents was still drastically decreased when WT and mutant p.Arg518His-GluN2A subunits were co-expressed, suggesting a dominant-negative mechanism. Activation times were significantly decreased in both homozygous and heterozygous conditions for the two p.Ile184Ser and p.Arg518His variants, but not for p.Ala716His. Deactivation also significantly increased for p.Ile184Ser variant in the homozygous but not the heterozygous state while it was increased for p.Arg518His in both states. Our data indicate that p.Ile184Ser and p.Arg518His GluN2A variants both impacted on NMDAR function, albeit differently, whereas p.Ala716His did not significantly influence NMDAR kinetics, hence partly questioning its direct and strong pathogenic role. This study brings new insights into the functional impact that GRIN2A variants might have on NMDAR kinetics, and provides a mechanistic explanation for the neurological manifestations seen in the corresponding human spectrum of disorders.

Genetic variants of the glutamate activated N-methyl-D-aspartate (NMDA) receptor (NMDAR) subunit GluN2A are associated with the hyperexcitable states manifested by epileptic seizures and interictal discharges in patients with disorders of the epilepsyaphasia spectrum (EAS). The variants found in sporadic cases and families are of different types and include microdeletions encompassing the corresponding GRIN2A gene as well as nonsense, splice-site and missense GRIN2A defects. They are located at different functional domains of GluN2A and no clear genotype-phenotype correlation has emerged yet. Moreover, GluN2A variants may be associated with phenotypic pleiotropy. Deciphering the consequences of pathogenic GRIN2A variants would surely help in better understanding of the underlying mechanisms. This emphasizes the need for functional studies to unravel the basic functional properties of each specific NMDAR variant. In the present study, we have used patch-clamp recordings to evaluate kinetic changes of mutant NMDARs reconstituted after co-transfection of cultured cells with the appropriate expression vectors. Three previously identified missense variants found in patients or families with disorders of the EAS and situated in the N-terminal domain (p.Ile184Ser) or in the ligand-binding domain (p.Arg518His and p.Ala716Thr) of GluN2A were studied in both the homozygous and heterozygous conditions. Relative surface expression and current amplitude were significantly reduced for NMDARs composed of mutant p.Ile184Ser and p.Arg518His, but not p.Ala716His, as compared with wild-type (WT) NMDARs. Amplitude of whole-cell currents was still drastically decreased when WT and mutant p.Arg518His-GluN2A subunits were co-expressed, suggesting a dominant-negative mechanism. Activation times were significantly decreased in both homozygous and heterozygous conditions for the two p.Ile184Ser and p.Arg518His variants, but not for p.Ala716His. Deactivation also significantly increased for p.Ile184Ser variant in the homozygous but not the heterozygous state while it was increased for p.Arg518His in both states. Our data indicate that p.Ile184Ser and p.Arg518His GluN2A variants both impacted on NMDAR function, albeit differently, whereas p.Ala716His did not significantly influence NMDAR kinetics, hence partly questioning its direct and strong pathogenic role. This study brings new insights into the functional impact that GRIN2A variants might have on NMDAR kinetics, and provides a mechanistic explanation for the neurological manifestations seen in the corresponding human spectrum of disorders. [ABSTRACT FROM AUTHOR]

Objective To delineate the genetic, neurodevelopmental and epileptic spectrum associated with GRIN2A alterations with emphasis on epilepsy treatment. Methods Retrospective study of 19 patients (7 females; age: 1–38 years; mean 10.1 years) with epilepsy and GRIN2A alteration. Genetic variants were classified according to the guidelines and recommendations of the American College of Medical Genetics (ACMG). Clinical findings including epilepsy classification, treatment, EEG findings, early childhood development and neurodevelopmental outcome were collected with an electronic questionnaire. Results 7 out of 19 patients fulfilled the ACMG-criteria of carrying “pathogenic” or “likely pathogenic variants”, in twelve patients the alterations were classified as variants of unknown significance. The spectrum of pathogenic/likely pathogenic mutations was as follows: nonsense n = 3, missense n = 2, duplications/deletions n = 1 and splice site n = 1. First seizures occurred at a mean age of 2.4 years with heterogeneous seizure types. Patients were treated with a mean of 5.6 AED. 4/5 patients with VPA had an improved seizure frequency (n = 3 with a truncation: n = 1 missense). 3/5 patients with STM reported an improvement of seizures (n = 2 truncation, n = 1 splicing). 3/5 CLB patients showed an improvement (n = 2: truncation; n = 1 splicing). Steroids were reported to have a positive effect on seizure frequency in 3/5 patients (n = 1 each truncation, splicing or deletion). Conclusions Our data indicate that children with epilepsy due to pathogenic GRIN2A mutations present with different clinical phenotypes and a spectrum of seizure types in the context of a pharmacoresistant epilepsy providing information for clinicians treating children with this form of genetically determined epileptic syndrome. [ABSTRACT FROM AUTHOR]

Caffeine is neuroprotective in animal models of Parkinson's disease (PD) and caffeine intake is inversely associated with the risk of PD. This association may be influenced by the genotype of GRIN2A , which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p = 0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD. [ABSTRACT FROM AUTHOR]

Lead acts as an antagonist of the N-methyl-d-aspartate receptor (NMDAR). GRIN2A encodes an important subunit of NMDARs and may be a critical factor in the mechanism of lead neurotoxicity. Changes in GRIN2A expression levels or gene variants may be mechanisms of lead-induced neurotoxicity. In this study, we hypothesized that GRIN2A might contribute to lead-induced neurotoxicity. A preliminary HEK293 cell experiment was performed to analyze the association between GRIN2A expression and lead exposure. In addition, in a population-based study, serum GRIN2A levels were measured in both lead-exposed and control populations. To detect further the influence of GRIN2A gene single nucleotide polymorphisms (SNPs) in lead-induced neurotoxicity, 3 tag SNPs (rs2650429, rs6497540, and rs9302415) were genotyped in a case-control study that included 399 lead-exposed subjects and 398 controls. Lead exposure decreased GRIN2A expression levels in HEK293 cells (p < 0.001) compared with lead-free cells. Lead-exposed individuals had lower serum GRIN2A levels compared with controls (p < 0.001), and we found a trend of decreasing GRIN2A level with an increase in blood lead level (p < 0.001). In addition, we found a significant association between rs2650429 CT and TT genotypes and risk of lead poisoning compared with the rs2650429 CC genotype (adjusted odds ratio = 1.42, 95% confidence interval = 1.01–2.00]. Therefore, changes in GRIN2A expression levels and variants may be important mechanisms in the development of lead-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

The short arm of chromosome 16 is one of the less stable regions of our genome, as over 10% of the euchromatic region of 16p is composed of highly complex low copy repeats that are known to be predisposed to rearrangements mediated by non-allelic homologous recombination. The 16p13.3p13.13 molecular region has been defined as the 16p duplication hotspot, and duplications of chromosome 16p13 have recently been confirmed to cause a recognizable syndrome, with CREBBP being the main phenotype-causing gene. To date, only one case report is present in the literature with a 16p13 duplication without CREBBP involvement; we describe here a second analogous case with a not previously reported 16p13.2p13.13 microduplication. This paper allows us to better delineate the clinical features of 16p13 microduplications that do not encompass CREBBP and, concurrently, to narrow the molecular region responsible for congenital heart defects in 16p duplications as well as to propose GRIN2A as a candidate gene for epilepsy. [ABSTRACT FROM AUTHOR]

Human use of marijuana at an early age has been reported to lead to cognitive impairment. However, researchers have not yet clearly determined whether this impairment is due to marijuana-induced alterations in the developing nervous system and whether this deficit persists into adulthood after marijuana use has ceased. We administered anandamide to developing rats to assess the effect of cannabinoids on development. We subsequently evaluated learning and performance on a temporal bisection task in adulthood and assessed the expression of genes encoding principal subunits of NMDA receptors (Grin1, Grin2A, and Grin2B) in the hippocampus and prefrontal cortex. Rats in two age groups, namely, 21-day-old and 150-day-old rats, received intraperitoneal injections of anandamide or the vehicle for 14 days. Both groups performed a temporal bisection test, which included listening to tones of different durations and classifying them as short or long. The expression of the Grin1, Grin2A and Grin2B mRNAs was evaluated using quantitative PCR in both age groups after extracting mRNA from the hippocampus and prefrontal cortex. We observed a learning impairment in the temporal bisection task (p < 0.05) and changes in the response latency (p < 0.05) in rats that received anandamide. Furthermore, these rats exhibited decreased expression of Grin2b (p = 0.001) compared to those that received the vehicle. In human subjects, the use of cannabinoids during development induces a long-term deficit, but this deficit is not observed in subjects who use cannabinoids in adulthood. Rats treated with anandamide earlier in development took longer to learn the task, suggesting that anandamide exerts a harmful effect on cognition in developing rats. Administration of anandamide during early stages of development induced deficits in learning and other cognitive processes that depend on an adequate estimation of time. The cognitive demands of the environment must be considered when evaluating the cognitive effects of cannabinoids on developing or mature brains. High cognitive demands might induce differential expression of NMDA receptors that improves cognitive capacity, overcoming altered glutamatergic function • Administration of cannabinoids during early stages of development induced permanent deficits in learning and other cognitive processes. • Cannabinoids induce a different expression of NMDA subunits in Young subjects in comparation to the adults rats. • Cognitive processes depend on an adequate estimation of time, the observed deficit could be related to increase in temporal perception by cannabinoids. [ABSTRACT FROM AUTHOR]