A novel missense mutation in <i>GRIN2A</i> causes a nonepileptic neurodevelopmental disorder

Fernández–Marmiesse, Ana; Kusumoto, Hirofumi; Rekarte, Saray; Roca, Iria; Zhang, Jin; Myers, Scott J.; Traynelis, Stephen F.; Couce, María L.; Gutiérrez-Solana, Luis González; Yuan, Hongjie

doi:10.1002/mds.27315

Cited by 30 publications

(30 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Observing an effect of the variant despite the presence of wild-type subunits further supports a role for GluN2A N615K in disease causation. This finding indirectly supports the disease relevance of other NMDA receptor pore mutations where functional consequences have been established in diheteromers (Fedele et al 2018;Fernández-Marmiesse et al 2018).…”

Section: Glun2a N615k Reduces Mg 2+ Blockadesupporting

confidence: 72%

Functional assessment of triheteromeric NMDA receptors containing a human variant associated with epilepsy

Marwick

Hansen

Skehel

et al. 2019

The Journal of Physiology

View full text Add to dashboard Cite

Key points NMDA receptors are neurotransmitter‐gated ion channels that are critically involved in brain cell communication Variations in genes encoding NMDA receptor subunits have been found in a range of neurodevelopmental disorders. We investigated a de novo genetic variant found in patients with epileptic encephalopathy that changes a residue located in the ion channel pore of the GluN2A NMDA receptor subunit. We found that this variant (GluN2A N615K ) impairs physiologically important receptor properties: it markedly reduces Mg 2+ blockade and channel conductance, even for receptors in which one GluN2A N615K is co‐assembled with one wild‐type GluN2A subunit. Our findings are consistent with the GluN2A N615K mutation being the primary cause of the severe neurodevelopmental disorder in carriers. Abstract NMDA receptors are ionotropic calcium‐permeable glutamate receptors with a voltage‐dependence mediated by blockade by Mg 2+ . Their activation is important in signal transduction, as well as synapse formation and maintenance. Two unrelated individuals with epileptic encephalopathy carry a de novo variant in the gene encoding the GluN2A NMDA receptor subunit: a N615K missense variant in the M2 pore helix ( GRIN2A C1845A ). We hypothesized that this variant underlies the neurodevelopmental disorders in carriers and explored its functional consequences by electrophysiological analysis in heterologous systems. We focused on GluN2A N615K co‐expressed with wild‐type GluN2 subunits in physiologically relevant triheteromeric NMDA receptors containing two GluN1 and two distinct GluN2 subunits, whereas previous studies have investigated the impact of the variant in diheteromeric NMDA receptors with two GluN1 and two identical GluN2 subunits. We found that GluN2A N615K ‐containing triheteromers showed markedly reduced Mg 2+ blockade, with a value intermediate between GluN2A N615K diheteromers and wild‐type NMDA receptors. Single‐channel conductance was reduced by four‐fold in GluN2A N615K diheteromers, again with an intermediate value in GluN2A N615K ‐containing triheteromers. Glutamate deactivation rates were unaffected. Furthermore, we expressed GluN2A N615K in cultured primary mouse cortical neurons, observing a decrease in Mg 2+ blockade and reduction in current density, confirming that the variant continues to have significant functional impact in neuronal systems. Our results ...

show abstract

Section: Glun2a N615k Reduces Mg 2+ Blockadesupporting

confidence: 72%

Functional assessment of triheteromeric NMDA receptors containing a human variant associated with epilepsy

Marwick

Hansen

Skehel

et al. 2019

The Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…Enrichment was performed using in-solution hybridization technology (Sure Select XT; Agilent Technologies, Santa Clara, California) and subsequent sequencing using Miseq or NextSeq platforms (Illumina, Santa Clara, California), as previously described (Fernández-Marmiesse et al, 2018). Image analysis and processing of the fluorescence intensities in sequences (“base calling”) was performed with Real Time Analysis (RTA) software v.1.8.70 (Illumina), and FastQC v0.11.8 program was used for data quality control (Babraham Bioinformatics-FastQC A Quality Control Tool for High Throughput Sequence Data, 2018).…”

Section: Methodsmentioning

confidence: 99%

Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients

et al. 2019

Self Cite

View full text Add to dashboard Cite

In order to characterize the genetic architecture of epilepsy in a pediatric population from the Iberian Peninsula (including the Canary Islands), we conducted targeted exome sequencing of 246 patients with infantile-onset seizures with or without neurodevelopmental delay. We detected 107 variants in 48 different genes, which were implicated in neuronal excitability, neurodevelopment, synaptic transmission, and metabolic pathways. In 104 cases (42%) we detected variant(s) that we classified as pathogenic or likely pathogenic. Of the 48 mutated genes, 32 were dominant, 8 recessive and 8 X-linked. Of the patients for whom family studies could be performed and in whom pathogenic variants were identified in dominant or X-linked genes, 82% carried de novo mutations. The involvement of small copy number variations (CNVs) is 9%. The use of progressively updated custom panels with high mean vertical coverage enabled establishment of a definitive diagnosis in a large proportion of cases (42%) and detection of CNVs (even duplications) with high fidelity. In 10.5% of patients we detected associations that are pending confirmation via functional and/or familial studies. Our findings had important consequences for the clinical management of the probands, since a large proportion of the cohort had been clinically misdiagnosed, and their families were subsequently able to avail of genetic counseling. In some cases, a more appropriate treatment was selected for the patient in question, or an inappropriate treatment discontinued. Our findings suggest the existence of modifier genes that may explain the incomplete penetrance of some epilepsy-related genes. We discuss possible reasons for non-diagnosis and future research directions. Further studies will be required to uncover the roles of structural variants, epimutations, and oligogenic inheritance in epilepsy, thereby providing a more complete molecular picture of this disease. In summary, given the broad phenotypic spectrum of most epilepsy-related genes, efficient genomic tools like the targeted exome sequencing panel described here are essential for early diagnosis and treatment, and should be implemented as first-tier diagnostic tools for children with epilepsy without a clear etiologic basis.

show abstract

“…Other, refers to chromosome deletions, insertions, duplications that affect GRIN2A or GRIN2B genes. References 21, 73, 75, 76, 80, 82– 86, 89– 92, 94, 96, 98– 101, 103– 153.…”

Section: Comparison Of Patient Phenotype For Grin2a and Grin2b Missenmentioning

confidence: 99%

“…Nevertheless, these approaches have discovered a large number of de novo variants in neurological patients. A functional analysis has been published in the peer-reviewed literature for a number of GRIN2A variants 73, 75, 79, 83, 86, 90– 93 . In addition, there is a comprehensive functional summary on the websites as a resource ( http://functionalvariants.emory.edu).…”

Section: Comparison Of Patient Phenotype For Grin2a and Grin2b Missenmentioning

confidence: 99%

Distinct roles of GRIN2A and GRIN2B variants in neurological conditions

et al. 2019

Self Cite

View full text Add to dashboard Cite

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.

show abstract

A novel missense mutation in GRIN2A causes a nonepileptic neurodevelopmental disorder

Abstract: De novo GRIN2A mutations can give rise to a neurodevelopmental and movement disorder without epilepsy. © 2018 International Parkinson and Movement Disorder Society.

Cited by 30 publications

References 46 publications

Functional assessment of triheteromeric NMDA receptors containing a human variant associated with epilepsy

Functional assessment of triheteromeric NMDA receptors containing a human variant associated with epilepsy

Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients

Distinct roles of GRIN2A and GRIN2B variants in neurological conditions

Contact Info

Product

Resources

About