Genetics and pathobiology of ichthyosis en confetti

描述（由申请人提供）：该项目的目的是确定在五彩鱼鳞病的临床亚型中负责鳞状皮肤发展的基因突变，并在体外和通过小鼠模型的生成表征这些基因的功能。五彩鱼鳞病是一种明显的常染色体显性鱼鳞病，具有三种不同的临床变体，具有其他鱼鳞病或遗传性皮肤病所未见的特征-儿童时期数百个区域的发育逆转，正常皮肤在患者一生中数量和大小增加。我们利用这一临床发现设计了一种新的方法来绘制I型五彩鱼鳞病的位点，这种疾病由于遗传适应度受损和缺乏扩展类而无法通过传统的遗传分析方法进行分析。我们预测，五彩鱼鳞病最有可能是由杂合突变引起的，而高频率的逆转只能通过删除或丢失致病突变来实现，通过对从反向白点制备的DNA进行单核苷酸多态性阵列分析，与来自患者匹配的白细胞来源的DNA的DMA相比，可以通过识别杂合缺失的重叠区域来绘制疾病位点。在这样的分析中，我们已经在6例I型五彩鱼鳞病患者的28个白点中发现了17号染色体片段上的大重叠缺失，并且在进一步的研究中，我们已经证明了大多数这些逆转斑点的遗传校正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一个额外的临床变异，并期望确定一个额外的遗传位点。导致这两种类型鱼鳞病的基因突变将通过定位候选基因方法进行鉴定。该疾病的体外和小鼠模型将被研究，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，这些可能允许深入了解皮肤中逆转嵌合的机制，这可能对其他疾病有广泛的应用。该项目旨在为PI提供分子遗传学方面的培训，并使他能够在皮肤病学术领域发展事业，重点研究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.