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首页> 外文期刊>The Journal of investigative dermatology. >Structural and functional consequences of loricrin mutations in human loricrin keratoderma (vohwinkel syndrome with ichthyosis).
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Structural and functional consequences of loricrin mutations in human loricrin keratoderma (vohwinkel syndrome with ichthyosis).

机译：人Loricrin角化皮病（vohwinkel综合征鱼鳞病）中loricrin突变的结构和功能后果。

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摘要

Although loricrin is the predominant protein of the cornified envelope (CE) in keratinocytes, loss or gain of loricrin function in mouse models produces only modest skin phenotypes. In contrast, insertional mutations resulting in a frameshift in the C-terminal domain of loricrin produce the characteristic ichthyosis of loricrin keratoderma in mouse and man. To ascertain the basis for the loricrin keratoderma phenotype, we assessed epidermal structure and stratum corneum (SC) function in a previously genotyped human loricrin keratoderma kindred. Our studies revealed abnormal corneocyte fragility and basal permeability barrier function, but accelerated repair kinetics. Despite fragility, increased water loss occurred predominantly via extracellular domains, which correlated with disorganized lamellar bilayers that were linked spatially to discontinuities of the CE. Accelerated barrier recovery was explicable by amplified lamellar body secretion, while partial normalization of the CE in the outer SC correlated with persistence of abundant calcium in the extracellular spaces (positioned to activate transglutaminase-1). These results show that the barrier abnormality in loricrin keratoderma is linked to a defective CE scaffold, resulting in increased extracellular permeability, as shown previously for another "scaffold disorder", lamellar ichthyosis. But in contrast to lamellar ichthyosis, the CE scaffold partially normalizes in the outer SC in loricrin keratoderma.
机译：尽管Loricrin是角质形成细胞中角化包膜（CE）的主要蛋白质，但是在小鼠模型中loricrin功能的丧失或获得仅产生适度的皮肤表型。相反，导致loricrin C末端结构域移码的插入突变会在小鼠和人体内产生loricrin keratoderma特征性鱼鳞病。为了确定卢瑞林角蛋白表型的基础，我们评估了在先前基因分型的人卢瑞林角蛋白表皮中的表皮结构和角质层（SC）功能。我们的研究揭示了异常的角质细胞脆性和基础通透性屏障功能，但加速了修复动力学。尽管脆弱，但失水增加主要是通过细胞外区域发生的，这与在空间上与CE的不连续性相关的无序的层状双层相关。加速的屏障恢复可以通过扩大的层状体分泌来实现，而外部SC中CE的部分正常化与胞外空间中大量钙的持久存在有关（定位为激活转谷氨酰胺酶-1）。这些结果表明，铁蛋白角质层皮中的屏障异常与有缺陷的CE支架有关，导致增加的细胞外通透性，如先前针对另一种“支架疾病”即片状鱼鳞病所显示的。但是，与片状鱼鳞病相反，CE支架在Loricrin角皮病的外部SC中部分恢复正常。

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