Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans

Abstract

Ionotropic ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (iGluRs) mediate the majority of excitatory synaptic transmission in the CNS and are essential for the induction and maintenance of long-term potentiation and long-term depression, two cellular models of learning and memory. We identified a genomic deletion (0.4 Mb) involving the entire GRIA3 (encoding iGluR3) by using an X-array comparative genomic hybridization (CGH) and four missense variants (G833R, M706T, R631S, and R450Q) in functional domains of iGluR3 by sequencing 400 males with X-linked mental retardation (XLMR). Three variants were found in males with moderate MR and were absent in 500 control males. Expression studies in HEK293 cells showed that G833R resulted in a 78% reduction of iGluR3 due to protein misfolding. Whole-cell recording studies of iGluR3 homomers in HEK293 cells revealed that neither iGluR3-M706T (S2 domain) nor iGluR3-R631S (near channel core) had substantial channel function, whereas R450Q (S1 domain) was associated with accelerated receptor desensitization. When forming heteromeric receptors with iGluR2 in HEK293 cells, all four iGluR3 variants had altered desensitization kinetics. Our study provides the genetic and functional evidence that mutant iGluR3 with altered kinetic properties is associated with moderate cognitive impairment in humans.glutamate receptor ͉ X-linked mental retardation

Copy-number variations on the X chromosome in Japanese patients with mental retardation detected by array-based comparative genomic hybridization analysis

“…In addition, CUL4B (OMIM 300304) and GRIA3 (OMIM 305915), which were reported as XLMRassociated genes, 41,42 are located around the region involved (Supplementary Figure S4g). It is possible that the deletion alters expression levels through some mechanism, such as a defect in binding of transcription factor(s) and alteration of the chromatin structure.…”

Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials

“…72 In addition, one genetic study reported that GRIA3 gene mutations were related to moderate cognitive impairment in humans. 73 Furthermore, another line of evidence from animal studies has suggested a potentially compensatory role of AMPA receptors following NMDA receptor dysfunction. [74][75][76] For example, Jackson et al 77 demonstrated that an increase in glutamate efflux by NMDA antagonists stimulated cortical AMPA receptors.…”

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

“…For the GRIA gene family, there have been reports of a fusion transcript in GRIA2, a de novo interstitial deletion of chromosome 4q32 that contains the GRIA2 loci, missense mutations in the ligand binding and transmembrane domains of the GluA3 subunit (GRIA3), partial tandem duplication that reduced GRIA3 transcript levels, as well as frameshift in the GRIA3 gene ( Fig. 5; Supplemental Table S3) (Chiyonobu et al, 2007;Wu et al, 2007;Bonnet et al, 2009Bonnet et al, , 2012Poot et al, 2010;Tzschach et al, 2010;Hackmann et al, 2013;Philips et al, 2014). These data suggest that mutations within the GRIA gene family participate in a small subset of patients with intellectual disability; however, few cellular or mechanistic studies of these modifications have been reported.…”