Clinical and Functional Features of Epilepsy-Associated In-Frame Deletion Variants in SCN1A.
Clinical and Functional Features of Epilepsy-Associated In-Frame Deletion Variants in SCN1A.
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DOI：
10.3389/fnmol.2022.828846
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发表时间：
2022
影响因子：
4.8
通讯作者：
Su T
中科院分区：
文献类型：
--
作者：
Wang JY;Tang B;Sheng WX;Hua LD;Zeng Y;Fan CX;Deng WY;Gao MM;Zhu WW;He N;Su T
自然发生的框内缺失是一种独特类型的遗传变异，导致蛋白质中一个或多个氨基酸的丢失。癫痫相关基因SCN 1A编码电压门控钠通道α单位1.1（Nav1.1），在公共数据库中发现了大量的读框内缺失变异。与错义和截短变体相反，SCN 1A中的框内缺失在很大程度上仍然未被表征。我们总结了44个SCN 1A框内缺失变异的基本信息，并对我们癫痫病例中发现的6个变异进行了进一步分析。产生六个框内缺失的突变体和用作比较的一个截短变体，并在tsA 201细胞中与β-1和β-2亚基共转染，随后进行膜片钳记录。回顾所有的框内缺失显示它们遍布整个Nav1.1蛋白，没有明显的“热点”。主要类型（54%）为单一残留损失。缺失的长度和位置与临床表型无明显关系。6个框内缺失为2个单残基缺失（p.M400del和p.I1772del）、1个微缺失（p.S128_F130del）和3个大缺失（p.T303_R322del、p.T160_Y202del和p.V1335_V1428del）。它们分散并影响不同的功能结构域，包括跨膜螺旋、孔区和P环。电生理记录显示，没有可测量的钠电流在所有的六个突变体。相反，截短突变体p.M1619Ifs*7失去了一长段肽，保留了部分功能。这些缩短的异常突变体中的功能完全丧失表明Nav1.1蛋白是高度精确的结构，并且许多残基对离子电导没有冗余。框内缺失对蛋白质功能造成特别有害的影响，可能是由于有序残基的破坏。
Naturally occurring in-frame deletion is a unique type of genetic variations, causing the loss of one or more amino acids of proteins. A number of in-frame deletion variants in an epilepsy-associated gene SCN1A, encoding voltage gated sodium channel alpha unit 1.1 (Nav1.1), have been reported in public database. In contrast to the missense and truncation variants, the in-frame deletions in SCN1A remains largely uncharacterized. We summarized the basic information of forty-four SCN1A in-frame deletion variants and performed further analysis on six variants identified in our cases with epilepsy. Mutants of the six in-frame deletions and one truncating variant used as comparison were generated and co-transfected with beta-1 and -2 subunits in tsA201 cells, followed by patch clamp recordings. Reviewing all the in-frame deletions showed that they spread over the entire Nav1.1 protein, without obvious “hot spots.” The dominant type (54%) was single residue loss. There was no obvious relationship between the length or locations of deletions and their clinical phenotypes. The six in-frame deletions were two single residue deletions (p.M400del and p.I1772del), one microdeletion (p.S128_F130del) and three macrodeletions (p.T303_R322del, p.T160_Y202del, and p.V1335_V1428del). They scatter and affect different functional domains, including transmembrane helices, pore region, and P-loop. Electrophysiological recordings revealed no measurable sodium current in all of the six mutants. In contrast, the truncating mutant p.M1619Ifs*7 that loses a long stretch of peptides retains partial function. The complete loss-of-function in these shortened, abnormal mutants indicates that Nav1.1 protein is a highly accurate structure, and many of the residues have no redundancy to ion conductance. In-frame deletions caused particularly deleterious effect on protein function possibly due to the disruption of ordered residues.
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影响因子：
3.4
作者：
Favre, I;Moczydlowski, E;Schild, L
通讯作者：
Schild, L
影响因子：
9.8
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Meisler, MH
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作者：
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作者：
Gonsales, Marina C.;Montenegro, Maria Augusta;Lopes-Cendes, Iscia
通讯作者：
Lopes-Cendes, Iscia
影响因子：
6.1
作者：
Jones, Julie M.;Dionne, Louise;Meisler, Miriam H.
通讯作者：
Meisler, Miriam H.