Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy
Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy
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DOI：
10.1212/wnl.0000000000003309
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发表时间：
2016-11-08
期刊：
影响因子：
9.9
通讯作者：
Gecz, Jozef
中科院分区：
文献类型：
--
作者：
Corbett, Mark A.;Bellows, Susannah T.;Gecz, Jozef
目的：确定一个家族分离阵发性共济失调、婴儿惊厥和异质性癫痫的遗传基础，并研究 KCNA2 突变的表型谱。方法：对一个 3 代以上 7 名受影响个体的家族进行详细的表型分析。对患有癫痫性脑病 (EE) 的轻度受影响的祖母和她的孙子进行了全基因组测序。根据功能注释对分离变体进行过滤和优先排序。通过电压钳测定在体外和通过分子建模在计算机上分析突变对通道功能的影响。对 35 名具有异质表型的先证者进行 KCNA2 测序。结果：7 名家族成员患有阵发性共济失调 (5)、自限性婴儿癫痫发作 (5)、发展为遗传性全面性癫痫 (4)、局灶性癫痫发作 (2) 和 EE (1)。他们在摇床型电压门控钾通道 KCNA2 中存在分离新突变（CCDS_827.1：c.765_773del；p.255_257del）。在 2 名受影响的兄弟姐妹及其未受影响的母亲中也发现了一种罕见的错义 SCN2A (rs200884216) 变异。 p.255_257del 突变导致通道功能显性负性丧失。分子模型预测了电压传感域中关键精氨酸残基的重新定位。 KCNA2 测序显示，一名患有 EE、共济失调和震颤的女孩存在 1 个从头突变 (CCDS_827.1: c.890G>A; p.Arg297Gln)。结论：KCNA2 突变导致显性遗传性发作性共济失调、轻度婴儿期癫痫发作，以及后来在智力正常的情况下出现全身性和局灶性癫痫。这一观察结果扩展了通常与慢性共济失调相关的 EE 的 KCNA2 表型谱，反映了在许多离子通道疾病中观察到的严重程度的显着变化。
Objective: To identify the genetic basis of a family segregating episodic ataxia, infantile seizures, and heterogeneous epilepsies and to study the phenotypic spectrum of KCNA2 mutations.Methods: A family with 7 affected individuals over 3 generations underwent detailed phenotyping. Whole genome sequencing was performed on a mildly affected grandmother and her grandson with epileptic encephalopathy (EE). Segregating variants were filtered and prioritized based on functional annotations. The effects of the mutation on channel function were analyzed in vitro by voltage clamp assay and in silico by molecular modeling. KCNA2 was sequenced in 35 probands with heterogeneous phenotypes.Results: The 7 family members had episodic ataxia (5), self-limited infantile seizures (5), evolving to genetic generalized epilepsy (4), focal seizures (2), and EE (1). They had a segregating novel mutation in the shaker type voltage-gated potassium channel KCNA2 (CCDS_827.1: c.765_773del; p.255_257del). A rare missense SCN2A (rs200884216) variant was also found in 2 affected siblings and their unaffected mother. The p.255_257del mutation caused dominant negative loss of channel function. Molecular modeling predicted repositioning of critical arginine residues in the voltage-sensing domain. KCNA2 sequencing revealed 1 de novo mutation (CCDS_827.1: c.890G>A; p.Arg297Gln) in a girl with EE, ataxia, and tremor.Conclusions: A KCNA2 mutation caused dominantly inherited episodic ataxia, mild infantile-onset seizures, and later generalized and focal epilepsies in the setting of normal intellect. This observation expands the KCNA2 phenotypic spectrum from EE often associated with chronic ataxia, reflecting the marked variation in severity observed in many ion channel disorders.