title: Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases.
abstract: The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-d-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases.
authors.affiliation: Departments of Pharmacology (H.Y., A.J., S.F.T.) and Anesthesiology (O.A.M., A.J.), Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia; and Departments of Pharmacology and Anaesthesia, Yong Loo Lin School of Medicine, National University of Singapore Graduate School for Integrative Sciences and Engineering, and Neurobiology/Ageing Programme, National University of Singapore, Singapore (C.-M.L.).
authors.forename: Hongjie
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Departments of Pharmacology (H.Y., A.J., S.F.T.) and Anesthesiology (O.A.M., A.J.), Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia; and Departments of Pharmacology and Anaesthesia, Yong Loo Lin School of Medicine, National University of Singapore Graduate School for Integrative Sciences and Engineering, and Neurobiology/Ageing Programme, National University of Singapore, Singapore (C.-M.L.).
authors.forename: Chian-Ming
authors.initials: CM
authors.lastname: Low
authors.affiliation: Departments of Pharmacology (H.Y., A.J., S.F.T.) and Anesthesiology (O.A.M., A.J.), Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia; and Departments of Pharmacology and Anaesthesia, Yong Loo Lin School of Medicine, National University of Singapore Graduate School for Integrative Sciences and Engineering, and Neurobiology/Ageing Programme, National University of Singapore, Singapore (C.-M.L.).
authors.forename: Olivia A
authors.initials: OA
authors.lastname: Moody
authors.affiliation: Departments of Pharmacology (H.Y., A.J., S.F.T.) and Anesthesiology (O.A.M., A.J.), Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia; and Departments of Pharmacology and Anaesthesia, Yong Loo Lin School of Medicine, National University of Singapore Graduate School for Integrative Sciences and Engineering, and Neurobiology/Ageing Programme, National University of Singapore, Singapore (C.-M.L.).
authors.forename: Andrew
authors.initials: A
authors.lastname: Jenkins
authors.affiliation: Departments of Pharmacology (H.Y., A.J., S.F.T.) and Anesthesiology (O.A.M., A.J.), Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia; and Departments of Pharmacology and Anaesthesia, Yong Loo Lin School of Medicine, National University of Singapore Graduate School for Integrative Sciences and Engineering, and Neurobiology/Ageing Programme, National University of Singapore, Singapore (C.-M.L.) strayne@emory.edu.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
mesh_terms: D001665:Binding Sites; D002491:Central Nervous System Agents / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D009422:Nervous System Diseases / Q000188:drug therapy / Q000235:genetics*; D017434:Protein Structure, Tertiary; D018079:Receptors, GABA / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D058468:Receptors, Ionotropic Glutamate / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; D018079:Receptors, GABA; D058468:Receptors, Ionotropic Glutamate