GRIN2A-related disorders: genotype and functional consequence predict phenotype

Strehlow et al. describe the largest cohort to date of individuals with GRIN2A-related disorders. The results reveal two phenotypic subgroups associated with different classes of variants affecting distinct domains of the GluN2A protein with different functional consequences. The findings will help predict outcomes in newly diagnosed individuals.

[1]  R. Pagon,et al.  GRIN2A-Related Speech Disorders and Epilepsy -- GeneReviews® , 2019 .

[2]  Hongjie Yuan,et al.  De Novo Mutations and Rare Variants Occurring in NMDA Receptors. , 2018, Current opinion in physiology.

[3]  H. Mefford,et al.  De novo mutations in GRIN1 cause extensive bilateral polymicrogyria , 2018, Brain : a journal of neurology.

[4]  M. Daly,et al.  Regional missense constraint improves variant deleteriousness prediction , 2017, bioRxiv.

[5]  N. Burnashev,et al.  Functional Properties of Human NMDA Receptors Associated with Epilepsy-Related Mutations of GluN2A Subunit , 2017, Front. Cell. Neurosci..

[6]  Keith Nykamp,et al.  Sherloc: a comprehensive refinement of the ACMG–AMP variant classification criteria , 2017, Genetics in Medicine.

[7]  Anup D. Patel,et al.  GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects , 2017, Journal of Medical Genetics.

[8]  Stephen F. Traynelis,et al.  Functional Evaluation of a De Novo GRIN2A Mutation Identified in a Patient with Profound Global Developmental Delay and Refractory Epilepsy , 2017, Molecular Pharmacology.

[9]  D. Collier,et al.  Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency – molecular profiling and functional rescue , 2017, Scientific Reports.

[10]  A. Cohen,et al.  Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology , 2017, PLoS genetics.

[11]  Stephen F Traynelis,et al.  Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains. , 2016, American journal of human genetics.

[12]  Marni J. Falk,et al.  GRIN2D Recurrent De Novo Dominant Mutation Causes a Severe Epileptic Encephalopathy Treatable with NMDA Receptor Channel Blockers. , 2016, American journal of human genetics.

[13]  P. Paoletti,et al.  Altered zinc sensitivity of NMDA receptors harboring clinically-relevant mutations , 2016, Neuropharmacology.

[14]  I. Scheffer,et al.  GRIN2A-Related Speech Disorders and Epilepsy , 2016 .

[15]  D. Misceo,et al.  Delineating the GRIN1 phenotypic spectrum , 2016, Neurology.

[16]  James Y. Zou.  Analysis of protein-coding genetic variation in 60,706 humans , 2015, Nature.

[17]  Gal Chechik,et al.  Gene Expression Switching of Receptor Subunits in Human Brain Development , 2015, PLoS Comput. Biol..

[18]  Yan Lin,et al.  The GluN2B subunit of N-methy-D-asparate receptor regulates the radial migration of cortical neurons in vivo , 2015, Brain Research.

[19]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[20]  Shujia Zhu,et al.  Allosteric modulators of NMDA receptors: multiple sites and mechanisms. , 2015, Current opinion in pharmacology.

[21]  Stephen F Traynelis,et al.  GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine , 2014, Annals of clinical and translational neurology.

[22]  G. Hardingham,et al.  Influence of GluN2 subunit identity on NMDA receptor function , 2013, Neuropharmacology.

[23]  Anne de Saint Martin,et al.  GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction , 2013, Nature Genetics.

[24]  U. Stephani,et al.  Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes , 2013, Nature Genetics.

[25]  J. Shendure,et al.  GRIN2A mutations cause epilepsy-aphasia spectrum disorders , 2013, Nature Genetics.

[26]  Qiang Zhou,et al.  NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease , 2013, Nature Reviews Neuroscience.

[27]  G. Hardingham,et al.  TCN 201 selectively blocks GluN2A-containing NMDARs in a GluN1 co-agonist dependent but non-competitive manner , 2012, Neuropharmacology.

[28]  P. Kind,et al.  Pituitary adenylate cyclase-activating peptide induces long-lasting neuroprotection through the induction of activity-dependent signaling via the cyclic AMP response element-binding protein-regulated transcription co-activator 1 , 2011, Journal of neurochemistry.

[29]  J. Coyle,et al.  Glutamate receptor composition of the post-synaptic density is altered in genetic mouse models of NMDA receptor hypo- and hyperfunction , 2011, Brain Research.

[30]  H. Ropers,et al.  Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes , 2010, Nature Genetics.

[31]  R. Dingledine,et al.  Glutamate Receptor Ion Channels: Structure, Regulation, and Function , 2010, Pharmacological Reviews.