Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders.

Abstract

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.

• Authors: Jacob R Stolz, Kendall M Foote, Hermine E Veenstra-Knol, Rolph Pfundt, Sanne W Ten Broeke, Nicole de Leeuw, Laura Roht, Sander Pajusalu, Reelika Part, Ionella Rebane, Katrin Õunap, Zornitza Stark, Edwin P Kirk, John A Lawson, Sebastian Lunke, John Christodoulou, Raymond J Louie, R Curtis Rogers, Jessica M Davis, A Micheil Innes, Xing-Chang Wei, Boris Keren, Cyril Mignot, Robert Roger Lebel, Steven M Sperber, Ai Sakonju, Nienke Dosa, Daniela Q C M Barge-Schaapveld, Cacha M P C D Peeters-Scholte, Claudia A L Ruivenkamp, Bregje W van Bon, Joanna Kennedy, Karen J Low, Sian Ellard, Lewis Pang, Joseph J Junewick, Paul R Mark, Gemma L Carvill, Geoffrey T Swanson
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 108 Issue 9 Pg. 1692-1709 (09 02 2021) ISSN: 1537-6605 [Electronic] United States
• PMID: 34375587 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Receptors, Kainic Acid

Topics

• Adolescent
• Adult
• Alleles
• Brain (diagnostic imaging, metabolism, pathology)
• Child
• Child, Preschool
• Developmental Disabilities (diagnostic imaging, genetics, metabolism, pathology)
• Epilepsy (diagnostic imaging, genetics, metabolism, pathology)
• Evoked Potentials (physiology)
• Gene Expression Regulation, Developmental
• Genetic Association Studies
• Heterozygote
• Homozygote
• Humans
• Intellectual Disability (diagnostic imaging, genetics, metabolism, pathology)
• Ion Channel Gating
• Male
• Models, Molecular
• Mutation
• Neurons (metabolism, pathology)
• Protein Conformation
• Receptors, Kainic Acid (chemistry, genetics, metabolism)
• GluK2 Kainate Receptor