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.

Graphical abstract

Fig. 1.

Architecture and domain organization of ionotropic GABA_A receptor family. (A) Top-down and (B) side view of a homomeric β3 GABA_A receptor (PDB ID 4COF). (C) Linear representation of modular ligand-binding domain (blue) and TMD (yellow) within a subunit polypeptide chain. (D) Schematic illustration of a GABA_A receptor subunit topology with the extracellular domain (blue) and membrane-associated elements (yellow) color coded to match the linear polypeptide chain in (C). Short peptide linkers between domains are shown in black lines.

Fig. 2.

Architecture and domain organization of the ionotropic glutamate receptor family. (A) Top-down and (B) side view of an NMDA receptor (PDB ID 4PE5) (Karakas and Furukawa, 2014). (C) Linear representation of modular amino-terminal domain (green), ligand-binding domain (blue), TMD (yellow), and C-terminal domain (gray) within a subunit polypeptide chain. (D) Schematic illustration of a glutamate receptor subunit topology with the extracellular domain (blue and green) and membrane-associated elements (yellow) color coded to match the linear polypeptide chain in (C). Short peptide linkers between domains are shown in black lines.

Fig. 3.

Published human GRIN2A mutations in the coding sequence identified in neurologic disorders. S1 and S2 comprise the ligand-binding domain and M1–M4 comprise the transmembrane domains; see Fig. 2 for domain organization. fs* denotes a mutation leading to a frame shift. ATD, amino-terminal domain; CTD, carboxyl-terminal domain.

Fig. 4.

Functional analysis of GluN2A mutation (L812M) and personalized therapy. (A) Location of mutant L812M (green space fill) and possible van der Waals interaction with the adjacent GluN1 subunit pre-M1 helix (purple) and SYTANLAAF (yellow) of the NMDA receptor gate as predicted from the homomeric GluA2 structure. The GluN2A(L812M) mutation changes the pharmacology and channel properties of NMDA receptors and shows increased glutamate potency (B), prolonged deactivation time course (C), and increased open probability (D) with triheteromeric NMDA receptors, with 0, 1, or 2 copies of the L812M mutation in each complex (B–D reproduced from Yuan et al., 2014). (E) GluN2A(L812M) modestly reduces the sensitivity to the FDA-approved drug memantine. (F) Adjunct antiepileptic drug treatment with memantine reduced seizure frequency after progressive weaning off of lacosamide and rufinamide between weeks 40–60, whereas valproate dosing remained unchanged (E and F reproduced from Pierson et al., 2014; http://creativecommons.org/licenses/by/4.0/).

Fig. 5.

Published human GRIA, GRIK, and GRID mutations in the coding sequence identified in neurologic disorders. Refer to Fig. 2 for domain organization. ATD, amino-terminal domain; CTD, carboxyl-terminal domain.