Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 108, Issue 9, Pages 1692-1709Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2021.07.007
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Funding
- National Institute for Neurological Disorders and Stroke [R01NS105502, R00NS089858]
- Sydney Children's Hospital Network
- National Health and Medical Research Council [GNT1113531]
- Estonian Research Council [PRG471, MOBTP175, PUTJD827]
- Victorian Government's Operational Infrastructure Support Program
- Murphy family
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Variants in the GRIK2 gene can lead to a neurodevelopmental disorder characterized by intellectual disability and developmental delay, with different outcomes depending on mono-allelic or bi-allelic effects. Shared GRIK2 variants among patients are associated with overlapping behavioral and neurological dysfunctions, indicating the pathogenic nature of these mutations. Functional studies on mutant GRIK2 variants in Kainate receptors reveal complex effects on receptor properties and contribute to a better understanding of the role of KARs in early nervous system development.
Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.
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