Keratoderma- an Exploratory Study

描述（由申请人提供）：兜甲蛋白角化病与兜甲蛋白基因中的单核苷酸插入移码突变相关。这些移码突变导致 此外，还向兜甲蛋白质提供核定位信号，其导致兜甲蛋白在核中积累，在那里它产生尚不清楚的作用。其结果是一种极其衰弱的疾病，包括表皮角化过度、过度增殖、角化不全、核甲蛋白积聚和手指假性缺失（自体截肢）。小鼠研究支持突变型兜甲蛋白在疾病发病机制中的作用，因为表达突变型兜甲蛋白的小鼠显示疾病特征。然而，核兜甲蛋白如何影响事件以及核兜甲蛋白是否是疾病发病机制所必需的尚不清楚。此外，我们的知识是非常有限的细胞信号是如何改变角化病。我们已经开发了一种新的小鼠模型，其中我们抑制AP1转录因子信号传导。值得注意的发现是，这些小鼠显示出与人类角化病表型相匹配的表型。这包括表皮过度增生、角化过度、角化不全、核甲蛋白积聚以及尾部和趾假性隐翅。这在基底上表皮中的AP 1转录因子功能抑制后出现的事实强烈表明核兜甲蛋白积累、AP 1因子信号传导减少和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，可以扩展以前的发现，以了解核兜甲蛋白如何驱动角化病的病理学。我们提出了一个新的假设，即在表皮基底层上的细胞核积累的兜甲蛋白改变AP1转录因子在这些细胞中的信号，以驱动疾病的表型。

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.