A gain-of-function mutation in the GRIK2 gene causes neurodevelopmental deficits.
A gain-of-function mutation in the GRIK2 gene causes neurodevelopmental deficits.
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DOI：
10.1212/nxg.0000000000000129
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发表时间：
2017-02
期刊：
影响因子：
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通讯作者：
Swanson GT
中科院分区：
文献类型：
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作者：
Guzmán YF;Ramsey K;Stolz JR;Craig DW;Huentelman MJ;Narayanan V;Swanson GT
在一名表现为共济失调、运动和言语延迟以及智力残疾的10岁患者中，确定与一系列神经发育异常相关的遗传性或新生突变。我们对先证者及其父母进行了全外显子组测序。基于序列保守性、基因功能和与具有相似表型特征的疾病的关联，将致病基因变体鉴定为破坏性的。使用异源表达系统在体外对突变蛋白进行功能表征。GRIK2基因中的一个单一的从头点突变被确定为先证者神经系统症状的病因。预测突变将GluK2红藻氨酸受体（KAR）亚基（离子型谷氨酸受体基因家族的成员）中第657位（A657 T）的丙氨酸密码子变为苏氨酸密码子。全细胞电压钳记录显示，KARs纳入GluK2（A657T）亚基显示深刻改变通道门控和组成型活性在名义上无谷氨酸的细胞外介质。在这项研究中，我们将GRIK2基因中的从头功能获得性突变与运动和高阶认知功能的缺陷相关联。这些结果表明，生理KAR功能的中断妨碍了神经系统的适当发育。
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. 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. 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. 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.