TY - JOUR T1 - Ionotropic GABA and Glutamate Receptor Mutations and Human Neurological Diseases JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.115.097998 SP - mol.115.097998 AU - Hongjie Yuan AU - Chian-Ming Low AU - Olivia A. Moody AU - Andrew Jenkins AU - Stephen F. Traynelis Y1 - 2015/04/22 UR - http://molpharm.aspetjournals.org/content/early/2015/04/22/mol.115.097998.abstract N2 - 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 neurological disorders by improving diagnoses, illuminating 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 neurological 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 NMDA receptor subunit being most often affected. These mutations are associated with multiple neurological 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 AMPA 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 GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurological diseases. ER -