Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.
Department of Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands.
Hum Mutat. 2018 Dec;39(12):1942-1956. doi: 10.1002/humu.23619. Epub 2018 Sep 13.
Variants in the SCN2A gene cause a broad spectrum of epilepsy syndromes of variable severity including benign neonatal-infantile epilepsy (BFNIE), developmental and epileptic encephalopathies (DEE), and other neuropsychiatric disorders. Here, we studied three newly identified variants, which caused distinct phenotypes observed in nine affected individuals of three families, including BFNIE, and DEE with intractable neonatal seizures. Whole cell patch-clamp recordings of transfected tsA201 cells disclosed an increased current density and an increased subthreshold sodium inward current upon an action potential stimulus (p.(Lys908Glu)), a hyperpolarizing shift of the activation curve (p.(Val208Glu) and p.(Thr773Ile)), and an increased persistent current (p.(Thr773Ile)). To evaluate genotype-phenotype correlations, we next developed scoring systems for both the extent of the electrophysiological dysfunction and the severity of the clinical phenotype and applied those to 21 previously and newly functionally characterized SCN2A variants. All inherited variants were associated with a mild clinical phenotype and a lower electrophysiological score compared to those occurring de novo and causing severe phenotypes. Our results thus reveal a nice correlation between the extent of channel dysfunction and the clinical severity.
SCN2A 基因突变可导致广泛的癫痫综合征，严重程度不一，包括良性新生儿-婴儿癫痫（BFNIE）、发育性和癫痫性脑病（DEE）和其他神经精神障碍。在这里，我们研究了三个新发现的变异，它们导致了三个家族的九个受影响个体中观察到的不同表型，包括 BFNIE 和 DEE 伴新生儿难治性癫痫发作。转染 tsA201 细胞的全细胞膜片钳记录显示，在动作电位刺激时，电流密度增加，阈下钠内流增加（p.(Lys908Glu)），激活曲线的超极化偏移（p.(Val208Glu)和 p.(Thr773Ile)），以及持续电流增加（p.(Thr773Ile)）。为了评估基因型-表型相关性，我们接下来为电生理功能障碍的程度和临床表型的严重程度开发了评分系统，并将其应用于 21 个先前和新功能表征的 SCN2A 变异体。与从头发生和引起严重表型的变异体相比，所有遗传变异体与较轻的临床表型和较低的电生理评分相关。因此，我们的研究结果揭示了通道功能障碍的程度与临床严重程度之间存在很好的相关性。
