Genomic analysis of patients with neurological conditions is becoming increasingly more common, providing a great deal of genomic data relating changes in patient DNA to neurological disease. However, the rate at which genetic mutations are identified has not been matched by advances in understanding the functional effects of these mutations on target proteins. For most genes, known disease-associated missense mutations far outnumber mutations for which functional data exists. Thus, a large gulf exists between the mutations we know about and our understanding of how individual mutations impact protein function. This gulf is growing wider with the accelerating pace of sequencing. While computational methods exist that predict which missense mutations may be harmful, these algorithms are a poor substitute for functional data. Thus, there is a critical need for a means by which clinically-oriented laboratories can obtain functional insight into the effects of mutations. This R24 proposal seeks to fill the gap between mutations and function for the ligand-gated glutamate receptor gene family, which includes AMPA, kainate, and NMDA receptors encoded by GRIA, GRIK, and GRIN genes, respectively. The decision to focus efforts on one gene family was made in consultation with NIH, and was driven by the budget for this funding opportunity. The number of known mutations in this family of genes encoding NMDA receptor subunits is growing at a fast pace, with well over a hundred novel disease- associated mutations described in just the past 18 months, and many more known but unpublished. Thus, while we will focus on all glutamate receptor mutations, we expect most mutations identified will be in the GRIN family. Interested investigators with glutamate receptor mutations will share the amino acid change, which will be introduced into commercial cDNAs for use in heterologous expressions systems to obtain functional data describing the effects of the mutation. The Resource Center will share this functional information with the clinical lab, and work to facilitate publication of the data. This effort will fill a critical gap in the literature, advance our understanding of neurological disease, and provide new ideas about future treatment paradigms. Three activities will be supported by this R24 resource grant. First, we will contact at least 100 laboratories performing whole exome/genome sequencing to inform them of this resource. Second, for clinics or investigators who have identified GRIN mutations and would like to obtain functional analysis, we will introduce the mutation into commercially available human cDNAs and functionally evaluate the effects of the mutation on agonist potency, modulator sensitivity, response time course, and receptor surface expression. Third, we will develop a searchable database on the web to archive results from this project, and connect our results with several existing databases (ClinVar, EGI, etc.).

Public Health Relevance

Ion channels mediate communication between neurons and thus play an important role in brain function and neurological diseases. An increasing number of human mutations and variants have been identified that alter channel function in ways that can perturb the balance of excitation and inhibition in the brain, leading to seizures and other neuropathological consequences, and there is a large gap between the vast number of mutations / variants that are known and our functional understanding of how these changes in protein structure alter channel function. This grant seeks to provide this missing functional data for known and newly identified rare variants and de novo mutations of the glutamate receptors for which data is currently unavailable; this information will allow those in the field to better connect functional phenotype to clinical symptoms, and advance our understanding of the contribution of these mutations to neurological disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Resource-Related Research Projects (R24)
Project #
5R24NS092989-03
Application #
9526571
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Silberberg, Shai D
Project Start
2016-08-01
Project End
2020-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Fry, Andrew E; Fawcett, Katherine A; Zelnik, Nathanel et al. (2018) De novo mutations in GRIN1 cause extensive bilateral polymicrogyria. Brain :
Fernández-Marmiesse, Ana; Kusumoto, Hirofumi; Rekarte, Saray et al. (2018) A novel missense mutation in GRIN2A causes a nonepileptic neurodevelopmental disorder. Mov Disord 33:992-999
Liu, Shuxi; Zhou, Liang; Yuan, Hongjie et al. (2017) A Rare Variant Identified Within the GluN2B C-Terminus in a Patient with Autism Affects NMDA Receptor Surface Expression and Spine Density. J Neurosci 37:4093-4102
Platzer, Konrad; Yuan, Hongjie; Schütz, Hannah et al. (2017) GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. J Med Genet 54:460-470
Ogden, Kevin K; Chen, Wenjuan; Swanger, Sharon A et al. (2017) Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology. PLoS Genet 13:e1006536
Gao, Kai; Tankovic, Anel; Zhang, Yujia et al. (2017) A de novo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia. PLoS One 12:e0170818
Chen, Wenjuan; Shieh, Christine; Swanger, Sharon A et al. (2017) GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function. J Hum Genet 62:589-597
Chen, Wenjuan; Tankovic, Anel; Burger, Pieter B et al. (2017) Functional Evaluation of a De Novo GRIN2A Mutation Identified in a Patient with Profound Global Developmental Delay and Refractory Epilepsy. Mol Pharmacol 91:317-330
Li, Dong; Yuan, Hongjie; Ortiz-Gonzalez, Xilma R et al. (2016) GRIN2D Recurrent De Novo Dominant Mutation Causes a Severe Epileptic Encephalopathy Treatable with NMDA Receptor Channel Blockers. Am J Hum Genet 99:802-816