Gene Expression Switching of Receptor Subunits in Human Brain Development

Bar-Shira, Ossnat; Maor, Ronnie; Chechik, Gal

doi:10.1371/journal.pcbi.1004559

Cited by 55 publications

(46 citation statements)

References 79 publications

(115 reference statements)

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“…The brain can tune the electrophysiological properties of synapses to regulate plasticity and information processing by switching from one protein variant to another. Such condition-dependent variant switch during development has been demonstrated in several neurotransmitter systems including NMDA and GABA 28 . Naturally, the question arises whether paralog conserved or non-conserved sites of the protein sequence are essential for function.…”

Section: Discussionmentioning

confidence: 92%

Gene family information facilitates variant interpretation and identification of disease-associated genes

Lal

Samocha

Kosmicki

et al. 2017

Preprint

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Differentiating risk-conferring from benign missense variants, and therefore optimal calculation of gene-variant burden, represent a major challenge in particular for rare and genetic heterogeneous disorders. While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes are paralogs and belong to gene families. It has not been thoroughly investigated how gene family information can be utilized for disease gene discovery and variant interpretation. We developed a paralog conservation score to empirically evaluate whether paralog conserved or nonconserved sites of in-human paralogs are important for protein function. Using this score, we demonstrate that disease-associated missense variants are significantly enriched at paralog conserved sites across all disease groups and disease inheritance models tested. Next, we assessed whether gene family information could assist in discovering novel disease-associated genes. We subsequently developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in more than 10k neurodevelopmental disorder patients. 33 gene family enriched genes represent novel candidate genes which are brain expressed and variant constrained in neurodevelopmental disorders.

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Section: Discussionmentioning

confidence: 92%

Gene family information facilitates variant interpretation and identification of disease-associated genes

Lal

Samocha

Kosmicki

et al. 2017

Preprint

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“…Genes in bold have not previously been reported as significantly enriched in exome-wide ASD, DD, or EPI studies (Continued) example, many receptors in the human brain consist of multiple protein subunits, many of which have multiple paralogs and are differentially expressed across brain regions and developmental stages. The brain can tune the electrophysiological properties of synapses to regulate plasticity and information processing by switching from one protein variant to another [34]. Such conditiondependent variant switch during development has been demonstrated in several neurotransmitter systems including NMDA and GABA [33].…”

Section: Discussionmentioning

confidence: 99%

Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

et al. 2020

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Background: Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. Methods: Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families. Results: We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint.

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“…The identity of the GluN2 subunits in the receptor impacts on receptor properties important in synaptic plasticity (Wyllie et al 2013). Diheteromeric GluN1/GluN2B receptors probably form the commonest forebrain receptor composition prenatally but, after GluN2A expression increases postnatally (Bar-Shira et al 2015), triheteromeric GluN1/GluN2A/GluN2B receptors comprise a major proportion of NMDA receptors, particularly in the hippocampus (Gray et al 2011;Rauner & Köhr, 2011;Tovar et al 2013).…”

Section: Introductionmentioning

confidence: 99%

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

Marwick

Hansen

Skehel

et al. 2019

The Journal of Physiology

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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 ...

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Gene Expression Switching of Receptor Subunits in Human Brain Development

Cited by 55 publications

References 79 publications

Gene family information facilitates variant interpretation and identification of disease-associated genes

Gene family information facilitates variant interpretation and identification of disease-associated genes

Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

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

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