Ichthyosis with confetti caused by new and recurrent mutations in KRT10 associated with varying degrees of keratin 10 mis-localization
Ichthyosis with confetti caused by new and recurrent mutations in KRT10 associated with varying degrees of keratin 10 mis-localization
复制标题
由与不同程度的角蛋白 10 错误定位相关的 KRT10 新突变和复发突变引起的五彩斑鱼鳞病
DOI：
10.1016/j.jdermsci.2020.02.005
复制
发表时间：
2020-04-01
影响因子：
4.6
通讯作者：
Lin, Zhimiao
中科院分区：
文献类型：
--
作者：
Pan, Yuxue;Feng, Cheng;Lin, Zhimiao
背景资料：摘要彩色纸屑鱼鳞病是一种极为罕见的常染色体显性遗传性皮肤病，其特征为红皮病并有许多彩色纸屑样的苍白斑点。IWC是由KRT 10（IWC-I）或KRT 1（IWC-II）中的突变引起的，这些突变会影响它们的尾部结构域。在IWC-I中，突变导致富含甘氨酸/丝氨酸的角蛋白10（K10）尾被富含精氨酸或丙氨酸的移码基序取代，导致K10错误定位，这可能通过有丝分裂重组引发突变KRT 10等位基因的丢失，导致遗传逆转。目的：研究5例IWC-I患者的突变及其功能后果。我们对5名患者的外周血样本中的KRT 1和KRT 10进行了桑格测序，并对KRT 10的高度多态性SNP进行了基因分型，以确认苍白斑表皮中的杂合性丢失。K10的表达模式进行了检查，在两个病人的皮肤活检和HaCaT细胞过表达突变KRT 10增强绿色荧光蛋白fusion.Results：四个新的和一个复发的KRT 10突变被确定在患者的外周血样本，但没有在相应的苍白点表皮。其中两个突变c.1696_1699dupCACA和c.1676dupG影响K10羧基端附近的残基，仅编码3个和6个精氨酸残基，远少于以前报道的。有趣的是，在HaCaT细胞过度表达这两个突变中的任何一个，并在相应的患者的受影响的皮肤中的K10的成像分析，显示了显着较低水平的K10的错误定位相比，其他突变在本study.Conclusions报告：我们的研究结果表明，精氨酸残基的突变体尾部的数量可能与IWC-I角质形成细胞中的K10的错误定位的水平。这些结果扩展了IWC-I的基因型和表型谱。(C)2020日本皮肤病研究学会。Elsevier B. V.出版，保留所有权利。
Background: Ichthyosis with confetti (IWC) is an extremely rare autosomal-dominant genodermatosis characterized by erythroderma with numerous confetti-like pale spots. IWC is caused by mutations in KRT10 (IWC-I) or KRT1 (IWC-II) which affect their tail domains. In IWC-I, the mutations lead to replacement of glycine/serine-rich keratin 10 (K10) tail with arginine- or alanine-rich frameshift motifs, causing K10 mis-localization which might trigger loss of the mutant KRT10 allele via mitotic recombination, leading to genetic reversion.Objective: To investigate mutations in five IWC-I patients and their functional consequences.Methods: We performed Sanger sequencing of KRT1 and KRT10 in peripheral blood samples of five patients, with highly polymorphic KRT10 SNPs genotyped to confirm loss-of-heterozygosity in the epidermis of pale spots. K10 expression pattern was examined in both patient skin biopsies and HaCaT cells overexpressing mutant KRT10-enhanced green fluorescence protein fusion.Results: Four novel and one recurrent KRT10 mutations were identified in patient peripheral blood samples but not in the corresponding pale spot epidermis. Two of the mutations, c.1696_1699dupCACA and c.1676dupG, affected residues close to K10 carboxyl terminus and encoded only 3 and 6 arginine residues, which were far fewer than reported previously. Interestingly, imaging analyses for K10 in HaCaT cells overexpressing either of these two mutations and in the corresponding patients' affected skin, showed a remarkably lower level of K10 mis-localization compared to that of other mutations reported in this study.Conclusions: Our findings suggest that the number of arginine residues in the mutant tail may correlate with the level of K10 mis-localization in IWC-I keratinocytes. These results expand the genotypic and phenotypic spectrum of IWC-I. (C) 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.