A novel de novo KCNB1 variant altering channel characteristics in a patient with periventricular heterotopia, abnormal corpus callosum, and mild seizure outcome
A novel de novo KCNB1 variant altering channel characteristics in a patient with periventricular heterotopia, abnormal corpus callosum, and mild seizure outcome
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DOI：
10.1038/s10038-022-01090-5
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发表时间：
2022-10
影响因子：
3.5
通讯作者：
Takuya Hiraide;T. Akita;Kenji Uematsu;Sachiko Miyamoto;M. Nakashima;Masayuki Sasaki;A. Fukuda;Mitsuhiro Kato;H. Saitsu
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文献类型：
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作者：
Takuya Hiraide;T. Akita;Kenji Uematsu;Sachiko Miyamoto;M. Nakashima;Masayuki Sasaki;A. Fukuda;Mitsuhiro Kato;H. Saitsu
KCNB1编码Kv2.1的α亚基，Kv2.1是神经元延迟整流钾电流的主要贡献者。该亚基由六个跨膜α螺旋（S1-S6）组成，包括电压敏感结构域（S1-S4）和孔结构域（S5-P-S6）。异源性KCNB1致病性变异与发育性和癫痫性脑病有关。在这里，我们报告一个人谁表现出较温和的表型相比，以前报道的情况下，包括语言发育迟缓，轻度智力残疾，注意缺陷多动障碍，迟发性癫痫反应的抗癫痫药物，血清肌酸激酶升高，周围轴突神经病变。另一方面，他的脑部MRI显示特征性发现，包括脑室周围异位、多小脑回和胼胝体异常。外显子组测序鉴定了一种新的KCNB1变异体c.574G> A，p.（Ala192Thr）位于电压敏感区S1段。在Neuro2a细胞中使用全细胞膜片钳技术进行的功能分析表明，Ala192Thr突变体在-50至-30 mV的膜电压范围内减少了通道的激活和失活。我们的病例可以扩大KCNB1变异患者的表型谱，并提示位于S1段的变异可能与癫痫发作的轻度结局相关。
KCNB1encodes the α-subunit of Kv2.1, the main contributor to neuronal delayed rectifier potassium currents. The subunit consists of six transmembrane α helices (S1–S6), comprising the voltage-sensing domain (S1–S4) and the pore domain (S5-P-S6). HeterozygousKCNB1pathogenic variants are associated with developmental and epileptic encephalopathy. Here we report an individual who shows the milder phenotype compared to the previously reported cases, including delayed language development, mild intellectual disability, attention deficit hyperactivity disorder, late-onset epilepsy responsive to an antiepileptic drug, elevation of serum creatine kinase, and peripheral axonal neuropathy. On the other hand, his brain MRI showed characteristic findings including periventricular heterotopia, polymicrogyria, and abnormal corpus callosum. Exome sequencing identified a novel de novoKCNB1variant c.574G>A, p.(Ala192Thr) located in the S1 segment of the voltage-sensing domain. Functional analysis using the whole-cell patch-clamp technique in Neuro2a cells showed that the Ala192Thr mutant reduces both activation and inactivation of the channel at membrane voltages in the range of −50 to −30 mV. Our case could expand the phenotypic spectrum of patients withKCNB1variants, and suggested that variants located in the S1 segment might be associated with a milder outcome of seizures.