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Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes
Molecular Medicine ( IF 5.7 ) Pub Date : 2019-02-27 , DOI: 10.1186/s10020-019-0073-6
Anaïs Begemann , Mario A. Acuña , Markus Zweier , Marie Vincent , Katharina Steindl , Ruxandra Bachmann-Gagescu , Annette Hackenberg , Lucia Abela , Barbara Plecko , Judith Kroell-Seger , Alessandra Baumer , Kazuhiro Yamakawa , Yushi Inoue , Reza Asadollahi , Heinrich Sticht , Hanns Ulrich Zeilhofer , Anita Rauch

BackgroundDeleterious variants in the voltage-gated sodium channel type 2 (Nav1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spectrum disorders (ASD). Yet, the underlying mechanisms are still incompletely understood.MethodsTo further elucidate the genotype-phenotype correlation of SCN2A variants we investigated the functional effects of six variants representing the phenotypic spectrum by whole-cell patch-clamp studies in transfected HEK293T cells and in-silico structural modeling.ResultsThe two variants p.L1342P and p.E1803G detected in patients with early onset epileptic encephalopathy (EE) showed profound and complex changes in channel gating, whereas the BFNIE variant p.L1563V exhibited only a small gain of channel function. The three variants identified in ID patients without seizures, p.R937C, p.L611Vfs*35 and p.W1716*, did not produce measurable currents. Homology modeling of the missense variants predicted structural impairments consistent with the electrophysiological findings.ConclusionsOur findings support the hypothesis that complete loss-of-function variants lead to ID without seizures, small gain-of-function variants cause BFNIE and EE variants exhibit variable but profound Nav1.2 gating changes. Moreover, structural modeling was able to predict the severity of the variant impact, supporting a potential role of structural modeling as a prognostic tool. Our study on the functional consequences of SCN2A variants causing the distinct phenotypes of EE, BFNIE and ID contributes to the elucidation of mechanisms underlying the broad phenotypic variability reported for SCN2A variants.

中文翻译:

进一步证实导致智力障碍或癫痫表型的 SCN2A 变异中不同的功能特征

背景电压门控钠通道 2 型 (Nav1.2) 中的有害变异导致广泛的表型,从良性家族性新生儿-婴儿癫痫 (BFNIE)、严重发育性和癫痫性脑病 (DEE) 和智力障碍 (ID) 到自闭症谱系障碍(ASD)。然而,潜在的机制仍然不完全清楚。 方法为了进一步阐明 SCN2A 变体的基因型-表型相关性,我们通过全细胞膜片钳研究在转染的 HEK293T 细胞和硅片结构中研究了代表表型谱的六种变体的功能影响。结果 在早发性癫痫性脑病 (EE) 患者中检测到的两个变体 p.L1342P 和 p.E1803G 显示通道门控的深刻而复杂的变化,而 BFNIE 变体 p. L1563V 仅表现出很小的通道功能增益。在没有癫痫发作的 ID 患者中发现的三种变异,p.R937C、p.L611Vfs*35 和 p.W1716*,没有产生可测量的电流。错义变异的同源建模预测结构损伤与电生理学发现一致。结论我们的研究结果支持这样的假设,即完全丧失功能的变异导致 ID 没有癫痫发作,小的功能获得变异导致 BFNIE 和 EE 变异表现出可变但意义深远Nav1.2 门控变化。此外,结构建模能够预测变异影响的严重程度,支持结构建模作为预后工具的潜在作用。我们对导致 EE 不同表型的 SCN2A 变体的功能后果的研究,
更新日期:2019-02-27
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