Dataset Information

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.

SUBMITTER: Stolz JR

PROVIDER: S-EPMC8456161 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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

Stolz Jacob R JR Foote Kendall M KM Veenstra-Knol Hermine E HE Pfundt Rolph R Ten Broeke Sanne W SW de Leeuw Nicole N Roht Laura L Pajusalu Sander S Part Reelika R Rebane Ionella I Õunap Katrin K Stark Zornitza Z Kirk Edwin P EP Lawson John A JA Lunke Sebastian S Christodoulou John J Louie Raymond J RJ Rogers R Curtis RC Davis Jessica M JM Innes A Micheil AM Wei Xing-Chang XC Keren Boris B Mignot Cyril C Lebel Robert Roger RR Sperber Steven M SM Sakonju Ai A Dosa Nienke N Barge-Schaapveld Daniela Q C M DQCM Peeters-Scholte Cacha M P C D CMPCD Ruivenkamp Claudia A L CAL van Bon Bregje W BW Kennedy Joanna J Low Karen J KJ Ellard Sian S Pang Lewis L Junewick Joseph J JJ Mark Paul R PR Carvill Gemma L GL Swanson Geoffrey T GT

American journal of human genetics 20210809 9

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 ...[more]

PMID: 34375587

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Dataset Information

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

Publications

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

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