背景:纸屑鱼鳞病(IWC)是一种极为罕见的常染色体显性遗传病,其特征是红皮病具有许多纸屑样苍白斑点。IWC是由KRT10(IWC-I)或KRT1(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)尾部被富含精氨酸或富含丙氨酸的移码基序取代,导致K10错误定位,这可能会通过有丝分裂重组引发突变KRT10等位基因的丢失,导致基因逆转。
目的:研究5例IWC-I患者的突变及其功能后果。
方法:我们对5例患者外周血样本中的KRT1和KRT10进行了Sanger测序,具有高度多态性的KRT10SNP基因分型,以确认苍白斑点表皮中杂合性的丧失。在患者皮肤活检和过表达突变KRT10增强的绿色荧光蛋白融合的HaCaT细胞中检查K10表达模式。
结果:在患者外周血样本中发现了4个新的和1个复发的KRT10突变,但在相应的浅斑表皮中未发现。其中两个突变,c.1696_1699dupCACA和c.1676dupG,影响靠近K10羧基末端的残基,仅编码3和6个精氨酸残基,比以前报道的要少得多。有趣的是,在过表达这两种突变的HaCaT细胞和相应的受影响的皮肤患者中,对K10进行影像学分析,与本研究中报道的其他突变相比,K10mis定位水平明显较低。
结论:我们的发现表明,突变尾部精氨酸残基的数量可能与IWC-I角质形成细胞中K10错误定位的水平相关。这些结果扩展了IWC-I的基因型和表型谱。
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.