In silico analysis of all point mutations on the 2B domain of K5/K14 causing epidermolysis bullosa simplex: a genotype-phenotype correlation
In silico analysis of all point mutations on the 2B domain of K5/K14 causing epidermolysis bullosa simplex: a genotype-phenotype correlation
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DOI：
10.1039/c4mb00138a
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发表时间：
2014-01-01
影响因子：
--
通讯作者：
Li, Chen
中科院分区：
文献类型：
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作者：
Banerjee, Santasree;Wu, Qian;Li, Chen
单纯性大疱性表皮病（EBS）是一种由角蛋白5和14（K5和K14）突变引起的遗传性皮肤病，导致基底角质形成细胞脆弱，最终导致表皮细胞溶解和起泡。根据症状的严重程度，EBS分为三种主要亚型。按照严重程度的增加顺序，这些类别是EBS，局限性（EBS-loc），EBS，其他全身性（EBS，gen-nonDM）和EBS，Dowling-Meara（EBS-DM）。我们已经搜索和组装了36个先前报道的位于K5/K14的2B结构域的点突变，以研究点突变的影响。通过进行全面的计算机分析，我们确定了突变及其表型效应之间的潜在关系。我们的研究结果表明，所有的致病点突变发挥其显性负效应的K5/K14卷曲螺旋异二聚体复合物通过改变链间的相互作用，导致异二聚体复合物的稳定性和组装能力的变化。取代氨基酸的理化性质和突变位置也与疾病严重程度密切相关。此外，我们发现了一个以前报道为非致病性的SNP（K14 p.M338R），由于链间相互作用和空间冲突的丧失，可能会影响二聚体结构的稳定性。总的来说，我们的研究结果表明，电子计算机表征的EBS严重程度的意义，并允许准确的遗传咨询和产前诊断。
Epidermolysis bullosa simplex (EBS) is a genodermatosis caused by mutations in keratins 5 and 14 (K5 and K14), which leads to fragility of basal keratinocytes and eventually epidermal cytolysis and blistering. Depending upon the severity of symptoms, EBS is classified into three major subtypes. In order of increasing severity these classes are EBS, localized (EBS-loc), EBS, other generalized (EBS, gen-nonDM), and EBS, Dowling-Meara (EBS-DM). We have searched and assembled 36 previously reported point mutations located on the 2B domain of K5/K14 in order to investigate the effects of point mutations. By performing a comprehensive in silico analysis we determine the underlying relationship between the mutation and its phenotypic effects. Our result showed that all pathogenic point mutations exert their dominant negative effect on the K5/K14 coiled-coil heterodimer complex by altering interchain interaction, leading to the changes in stability and assembly competence of the heterodimer complex. The physico-chemical properties of substituted amino acid and location of the mutation are also deeply correlated with disease severity. In addition, we found a SNP previously reported as non-pathogenic (K14 p.M338R) that likely affects the stability of the dimer structure due to the loss of interchain interaction and steric clashes. Overall, our finding demonstrates the significance of in silico characterization of EBS severity and would allow for accurate genetic counseling and prenatal diagnosis.