Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation
Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation
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DOI：
10.1093/hmg/ddu056
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发表时间：
2014-07-01
影响因子：
3.5
通讯作者：
Nelson, Stanley F.
中科院分区：
文献类型：
--
作者：
Lee, Hane;Lin, Meng-chin A.;Nelson, Stanley F.
大量的研究和病例报告显示自闭症和癫痫的共病，表明这两种表型有一些共同的分子基础。然而，在分子水平上，两者之间的关系仍不清楚。研究人员对一个患有自闭症和严重顽固性癫痫的同卵双胞胎家庭进行了全外显子组测序。在编码Kv4.2钾通道的KCND2基因中发现了一个新的变异。Kv4.2是躯体树突阈下a型钾电流（I-SA）通道中主要的成孔亚基。新突变p.Val404Met是一种新突变，发生在离子渗透途径跨膜螺旋S6区c末端的高度保守残基上。功能分析揭示了该变异可能的致病性，因为p.Val404Met突变体结构显示出显著的慢失活，无论是自身失活还是在与野生型Kv4.2通道结构等摩尔共表达后，都符合显性效应。此外，在与Kv4亚基结合形成体内I-SA通道的辅助亚基存在的情况下，突变对封闭状态失活的影响是明显的。功能相关的新变异的发现，加上突变蛋白破坏钾电流失活的生理证据，有力地支持KCND2是该家族癫痫的致病基因。KCND2与其他自闭症相关基因的相互作用以及KCND2在突触可塑性中的作用为自闭症的病因学作用提供了提示证据。
Numerous studies and case reports show comorbidity of autism and epilepsy, suggesting some common molecular underpinnings of the two phenotypes. However, the relationship between the two, on the molecular level, remains unclear. Here, whole exome sequencing was performed on a family with identical twins affected with autism and severe, intractable seizures. A de novo variant was identified in the KCND2 gene, which encodes the Kv4.2 potassium channel. Kv4.2 is a major pore-forming subunit in somatodendritic subthreshold A-type potassium current (I-SA) channels. The de novo mutation p.Val404Met is novel and occurs at a highly conserved residue within the C-terminal end of the transmembrane helix S6 region of the ion permeation pathway. Functional analysis revealed the likely pathogenicity of the variant in that the p.Val404Met mutant construct showed significantly slowed inactivation, either by itself or after equimolar coexpression with the wild-type Kv4.2 channel construct consistent with a dominant effect. Further, the effect of the mutation on closed-state inactivation was evident in the presence of auxiliary subunits that associate with Kv4 subunits to form I-SA channels in vivo. Discovery of a functionally relevant novel de novo variant, coupled with physiological evidence that the mutant protein disrupts potassium current inactivation, strongly supports KCND2 as the causal gene for epilepsy in this family. Interaction of KCND2 with other genes implicated in autism and the role of KCND2 in synaptic plasticity provide suggestive evidence of an etiological role in autism.