Genetics and pathobiology of ichthyosis en confetti

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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.