雪花状鱼鳞病高频回复突变的机理研究

雪花状鱼鳞病（IWC）是一种主要由KRT10基因突变导致的罕见遗传性皮肤病，主要表现为出生后全身红皮，以及随年龄增长逐渐增多的雪花状白斑。这些雪花状白斑实际上是皮肤组织的自我修复，每个白斑都是角质形成细胞（KC）发生各自独立的回复突变修复了IWC的致病性突变所致。既往研究认为IWC的突变体角蛋白10含有多聚精氨酸尾介导其异常进入细胞核，但具体机理不明。我们进一步研究发现，所有引起IWC的突变体角蛋白10尾部都包含一个13氨基酸的新短肽。我们提出假设，该13短肽可能通过促进KC快速增殖，同时加速KC凋亡来为高频回复突变提供细胞基数；同时13短肽还有可能通过入核干扰有丝分裂增加自发突变的频率。我们将设计体内外实验来验证这些假设。我们还将研究13短肽是否可以用于加速遗传性大疱性表皮松解症KC的回复突变。该研究将有利于弄清IWC高频回复突变发生机制，并且有望为其他遗传性皮肤病提供一种全新治疗途径。

Ichthyosis with confetti (IWC) is a rare genodermatosis caused by germline mutations in KRT10. IWC is characterized by generalized erytheroderma and progressively increased skin white spots. These numerous white spots are histopathologically normal skin with loss of germline mutations in KRT10, which results from independent somatic revertant mutations of keratinocytes. It was reported that poly-arginine in tail of the mutant keratin 10 is responsible for the high-frequent somatic revertant mutations in IWC. Based on our previous study, we found that all the IWC-associated KRT10 mutations harbored a 13-residue motif in the tail of keratin 10. We hypothesize that, this 13-residue motif might promote the proliferation as well as apoptosis of keratinocytes, which provide the cardinal number of cell population for high-frequent mutation rates of IWC keratinocytes. Meanwhile, it’s hypothesized that the 13-residue motif will be translocated to nucleus to accelerate the de novo mutations by binding to chromosomes and interfering mitosis of keratinocytes. These hypothesis will be verified by ex-vivo and in-vitro studies. We will also make efforts to determine while the 13-residue motif will accelerate the de novo revertant mutations of keratinocytes from patients with epidermolysis bullosa. Our study will probably clarify the underlying mechanism of high-frequent mutation rates in IWC, and open a new avenue for the treatment of genodermatosis.