Genetics and pathobiology of ichthyosis en confetti

描述（由申请人提供）：本项目的目的是鉴定在五彩纸屑鱼鳞病临床亚型中导致鳞状皮肤发展的基因突变，并通过体外和小鼠模型的产生来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，具有在其他鱼鳞病或遗传性皮肤病中未见的特征-在儿童期发育数百个回复突变的正常皮肤区域，这些区域在患者的一生中数量和大小增加。我们已经利用这一临床发现，设计了一种新的方法来定位I型鱼鳞病的基因座，这种疾病否则将无法通过传统的遗传分析方法，由于受损的遗传适应性和缺乏扩展的kinetics。我们预测五彩鱼鳞病最可能是由杂合突变引起的，并且高频率的回复突变只能通过致病突变的缺失或缺失来实现，从而允许通过在单核苷酸多态性阵列分析中鉴定由回复突变体白色斑点制备的DNA与来自患者匹配的白细胞来源的DNA的DNA相比的杂合性缺失的重叠区域来绘制疾病基因座。在这样的分析中，我们已经确定了大的重叠缺失的一段染色体17在28个白色斑点从6例I型鱼鳞病五彩纸屑，并在进一步的研究中，我们已经证明，在大多数这些回复突变点的遗传校正机制是有丝分裂重组。这是第一个通过这种途径实现如此广泛逆转的人类疾病的例子。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。负责这两种类型的鱼鳞病五彩纸屑的基因突变将被确定的位置候选基因的方法。将研究这种疾病的体外和小鼠模型，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的回复突变嵌合体的机制，这可能对其他疾病具有广泛的应用。该项目旨在为PI提供分子遗传学方面的培训，并使其能够在皮肤科学术领域开展工作，重点是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.