Genetics and pathobiology of ichthyosis en confetti

描述(申请人提供)：本项目的目的是确定导致五彩纸屑鱼鳞病临床亚型皮肤鳞屑形成的基因突变，并在体外和通过建立小鼠模型来表征这些基因的功能。五彩纸屑鱼鳞病是一种明显常染色体显性遗传的鱼鳞病，有三种不同的临床变种，具有其他鱼鳞病或遗传性皮肤病所没有的特征--儿童时期数百个区域的回复正常皮肤，随着患者一生的进程数量和大小不断增加。我们利用这一临床发现设计了一种新的方法来绘制I型五彩纸屑鱼鳞病的基因座图，这种疾病本来是无法通过传统的遗传分析方法获得的，因为遗传适合性受损和缺乏远亲。我们预测，五彩纸屑上的鱼鳞病最有可能是由杂合子突变引起的，而高频率的逆转只能通过删除或丢失致病突变来实现，通过在单核苷酸多态阵列分析中识别杂合性丢失的重叠区域来定位疾病基因座，与从患者匹配的白细胞来源的DNA制备的DNA相比，从突变白斑制备的DNA与DMA制备的DNA相比。在这样的分析中，我们在6例I型鱼鳞病患者的28个白斑中发现了17号染色体一段大的重叠缺失，并且在进一步的研究中，我们证明了这些回复斑点中的大多数遗传纠正的机制是有丝分裂重组。这是人类疾病通过这一途径实现如此广泛逆转的第一个例子。我们已经确定了这种疾病的另一种临床变异，并预计将确定另一种遗传位点。负责这两种类型的鱼鳞病的基因突变将通过位置候选基因方法进行鉴定。该疾病的体外和小鼠模型将进行研究，以确定这些基因在表皮分化中的正常和突变功能，但重要的是，这些研究可能有助于深入了解皮肤中突变马赛克的机制，这可能对其他疾病具有广泛的应用。这个项目旨在为PI提供分子遗传学方面的培训，并使他能够发展一名无刺皮肤病携带者，专注于遗传性皮肤病的分子遗传学。

DESCRIPTION (provided by applicant): The aim of this project is to identify the genetic mutations responsible for the development of scaly skin in the clinical subtypes of ichthyosis en confetti and to characterize the function of these genes in vitro and through the generation of mouse models. Ichthyosis en confetti is an apparently autosomal-dominant ichthyosis with three distinct clinical variants sharing a feature not seen in other ichthyoses or genodermatoses - the devel- opment of hundreds of areas of revertant, normal skin in childhood which increase in number and size over the course of a patient's lifetime. We have used this clinical finding to devise a novel approach to mapping the locus for type I ichthyosis en confetti, a disease which would otherwise have been unapproachable by traditional genetic analysis approaches due to impaired genetic fitness and a lack of extended kindreds. We predicted that ichthyosis en confetti is most likely to be caused by a heterozygous mutation and that the high frequency of reversion can only be accomplished by deletion or loss of the causative mutation, permitting mapping of the disease locus by identifying overlapping regions of loss of heterozygosity in single nucleotide polymorphism array analysis of DNA prepared from revertant white spots compared to DMA from patient- matched leukocyte-derived DNA. In such analysis, we have identified large overlapping deletions on a segment of chromosome 17 in 28 white spots from six patients with type I ichthyosis en confetti, and, in further studies, we have proven that the mechanism of genetic correction in the majority of these revertant spots is mitotic recombination. This is the first example of a human disease which achieves such widespread reversion via this pathway. We have identified an additional clinical variant of this disease and expect to identify an additional genetic locus. The genetic mutations responsible for the two types of ichthyosis en confetti will be identified by a positional candidate gene approach. In vitro and mouse models of this disease will be studied to identify the normal and mutant function of these genes in epidermal differentation, but, importantly, these may permit insight into mechanisms of revertant mosaicism in the skin which could have broad application to other diseases. This project is designed to provide training in moleclar genetics for the PI and to allow him to develop a carrer in acacdemic dermatology with a focus on the molecular genetics of heritable skin disease.