Keratoderma- an Exploratory Study

描述(申请人提供)：Loricrin角化病与Loricrin基因中的单核苷酸插入框架移位突变有关。这些移帧突变导致 此外，氯蛋白还有一个核定位信号，导致氯蛋白在细胞核内积聚，在那里它产生了尚不清楚的行为。结果是一种极其虚弱的疾病，即表皮过度角化、过度增殖、角化不全、核内氯化蛋白积聚和假性指(自体截肢)。小鼠研究支持突变的氯氯蛋白在疾病发病机制中的作用，因为表达突变氯氯蛋白的小鼠表现出疾病特征。然而，核氯化蛋白是如何影响事件的，以及核氯化氯化蛋白是否是疾病发病机制所必需的，目前还不清楚。此外，我们对角化皮肤病中细胞信号如何改变的了解非常有限。我们开发了一种新的小鼠模型，在该模型中，我们使AP1转录因子信号失活。值得注意的发现是，这些小鼠的表型与人类角化皮肤病的表型相匹配。这包括表皮过度增殖、角化过度、角化不全、核内氯化蛋白积聚以及尾部和趾部假性角化。这一事实是由于AP1转录因子在超基表皮中的转录功能被抑制而出现的，这有力地暗示了核氯丙烷积累、AP1因子信号转导减少与疾病发病机制之间的关系。这些小鼠代表了一个有趣的机会，可以扩展之前的发现，以了解核氯化蛋白如何可能驱动角化皮肤病的病理。我们提出了一个新的假说，即氯氯丙烷在表皮超基底层的核积累改变了这些细胞中的AP1转录因子信号，从而驱动了疾病的表型。

DESCRIPTION (provided by applicant): Loricrin keratoderma is associated with single nucleotide insertion frame-shift mutations in the loricrin gene. These frame-shift mutations result in addition of a nuclear localization signal to the loricrin protein which causes the loricrin to accumulate in the nucleus where it produces actions that are not understood. The outcome is an extremely debilitating disease of epidermal hyperkeratosis, hyperproliferation, parakeratosis, nuclear loricrin accumulation, and pseudoainhum (autoamputation) of the digits. Mouse studies support a role for mutant loricrin in disease pathogenesis as mutant loricrin-expressing mice display disease features. However, how nuclear loricrin influences events and whether nuclear loricrin is absolutely required for disease pathogenesis is not known. Moreover, our knowledge is very limited regarding how cell signaling is altered in keratoderma. We have developed a novel mouse model wherein we inactivate AP1 transcription factor signaling. The remarkable finding is that these mice display a phenotype that matches the human keratoderma phenotype. This includes epidermal hyperproliferation, hyperkeratosis, parakeratosis, nuclear loricrin accumulation, and tail and digit pseudoainhum. The fact that this appears upon inhibition of AP1 transcription factor function in the suprabasal epidermis, strongly suggests a relationship between nuclear loricrin accumulation, reduced AP1 factor signaling and disease pathogenesis. These mice represent an intriguing opportunity to extend previous discoveries to learn how nuclear loricrin may drive the pathology of keratoderma. We propose a novel hypothesis that nuclear accumulation of loricrin in the epidermal suprabasal layers alters AP1 transcription factor signaling in these cells to drive the disease phenotype.