Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders.
Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders.
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DOI：
10.1016/j.ajhg.2021.07.007
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发表时间：
2021-08
影响因子：
9.8
通讯作者：
Jacob R. Stolz;Kendall M. Foote;H. Veenstra-Knol;R. Pfundt;S. T. ten Broeke;N. de Leeuw;Laura Roht
中科院分区：
文献类型：
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作者：
Jacob R. Stolz;Kendall M. Foote;H. Veenstra-Knol;R. Pfundt;S. T. ten Broeke;N. de Leeuw;Laura Roht
红藻氨酸受体（KAR）是谷氨酸门控阳离子通道，在中枢神经系统中具有不同的作用。KAR编码基因GRIK 2的双等位基因功能缺失导致以智力残疾和发育迟缓为核心特征的非综合征性神经发育障碍（NDD）。GRIK 2单等位基因变异体在多大程度上也是NDD的基础还不太清楚，因为以前只报道了一个个体。在这里，我们描述了另外11个人与GRIK 2的异源性novovovovariants病因的神经发育缺陷，包括智力残疾。5名儿童携带复发的新变异体（3名编码p.Thr660Lys和2名编码p.Thr660Arg），4名儿童和1名成人为先前报道的变异体（c.1969G>A [p.Ala657Thr]）的杂合子。具有共同变异的个体有一些重叠的行为和神经功能障碍，这表明GRIK 2变异可能是致病的。在M3跨膜结构域（编码p.Ala657Thr、p.Thr660Lys和p.Thr660Arg）和M3-S2连接结构域（编码p.Ile668Thr）内的位点处引入重组GluK 2 KAR亚基的类似突变对同聚和异聚KAR的功能特性和膜定位具有复杂的影响。p.Thr660Lys和p.Thr660Arg突变体KAR均表现出明显减慢的门控动力学，类似于含p.Ala657Thr的受体。此外，我们观察到新兴的基因型-表型相关性，包括存在严重癫痫的个人与p.Thr660Lys的变异和低髓鞘形成的个人与p.Thr660Lys或p.Thr660Arg变异。总的来说，这些结果表明，预测改变通道功能的humanGRIK 2变异体是导致儿童早期发育障碍的原因，并进一步强调了阐明KAR在早期神经系统发育中的作用的重要性。
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 geneGRIK2causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants inGRIK2also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygousde novovariants inGRIK2causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrentde novovariants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were heterozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that theGRIK2variants 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 humanGRIK2variants 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.