A gain-of-function mutation in the GRIK2 gene causes neurodevelopmental deficits

Abstract

Objective:To identify inherited or de novo mutations associated with a suite of neurodevelopmental abnormalities in a 10-year-old patient displaying ataxia, motor and speech delay, and intellectual disability.Methods:We performed whole-exome sequencing of the proband and her parents. A pathogenic gene variant was identified as damaging based on sequence conservation, gene function, and association with disorders having similar phenotypic profiles. Functional characterization of the mutated protein was performed in vitro using a heterologous expression system.Results:A single de novo point mutation in the GRIK2 gene was identified as causative for the neurologic symptoms of the proband. The mutation is predicted to change a codon for alanine to that of a threonine at position 657 (A657T) in the GluK2 kainate receptor (KAR) subunit, a member of the ionotropic glutamate receptor gene family. Whole-cell voltage-clamp recordings revealed that KARs incorporating the GluK2(A657T) subunits show profoundly altered channel gating and are constitutively active in nominally glutamate-free extracellular media.Conclusions:In this study, we associate a de novo gain-of-function mutation in the GRIK2 gene with deficits in motor and higher order cognitive function. These results suggest that disruption of physiologic KAR function precludes appropriate development of the nervous system.

Unmasking GluN1/GluN3A excitatory glycine NMDA receptors

“…This is what is observed (Supplementary Figure 3). Unusual current phenotypes strikingly similar to those described here with constitutive activation, outward shifted steady-state currents and large tail currents have been recently described for kainate receptors harboring clinically-relevant mutations in their transmembrane region 53 . These effects are best explained by profoundly altered gating properties - exquisite sensitivity to ambient agonist (i.e.…”

“…These effects are best explained by profoundly altered gating properties - exquisite sensitivity to ambient agonist (i.e. glutamate) and reopening of receptors as they recover from desensitization 53 , 54 —as we propose here for glycine excitatory GluN1/GluN3A receptors under reducing conditions. The GluN3A-C859-C913 disulfide bridge occupies a strategic location in GluN3A 12 , 55 , connecting the ABD lower lobe to the TMD ion channel 56 , 57 .…”

Genetic and non-genetic factors associated with the phenotype of exceptional longevity & normal cognition

“…GRIK2 belongs to the kainate family of glutamate receptors that function as ligand-activated ion channels. This gene is highly expressed in brain and mutations in the gene have been associated with cortical development, autism and schizophrenia [60][61][62] . Interestingly, a large (6036 cases) genome-wide association study identified SNPs near GRIK2 as showing suggestive levels of association with longevity (OR = 1.2, p = 5.09e −8 ) 63 .…”

Interaction among GRIK2 gene on epilepsy susceptibility in Chinese children

“…Wang et al also suggested that GRIK2 gene was a candidate gene for epilepsy. Previously, some studies concluded that GRIK2 gene causes neurodevelopmental deficits and intellectual disability (ID) . GRIK2 was proposed as the genetic cause of isolated moderate to severe ID in an Iranian family .…”