Psoriasis is a chronic intractable skin disease, affecting approximately 2% of the population. We recently localized a gene for familial psoriasis susceptibility to the end of human chromosome 17q distal to D17S784. Heterogeneity testing suggested that 25-50% of the familial cases were attributed to a defect at this locus that is inherited in an autosomal dominant fashion. Penetrance of this defect in at least one large kindred is greater than 80%. Within this kindred psoriatic arthritis is also segregating with the psoriasis phenotype in four individuals. In this application an approach to identifying this psoriasis susceptibility gene is described. Additional families with multiple cases of psoriasis or with psoriatic arthritis will be genotyped for 17q-linked markers to refine the location of the susceptibility gene. Several candidate genes lie within this region. If they still remain within the region after additional physical mapping studies with radiation hybrids, mutations within these genes will be screened with SSCP and direct sequencing of genomic DNA or cDNA. If these candidate genes are excluded from being the susceptibility gene, we will isolate it with a positional cloning strategy utilizing technologies developed as a result of human genome research. This involves converting this region to yeast artificial chromosomes (YACs) and P1 phage by initially screening with STSs (sequence tagged sites) for closely linked polymorphic markers and genes. YACs will be converted to overlapping cosmids. Ongoing physical mapping efforts of genome centers working on this region will be utilized. Candidate genes will be isolated by direct screening of cDNA libraries and direct selection by hybridization with YACs, P1s and cosmids, and by exon-trapping of cosmids. A variety of cDNA sources will be used that include activated T-cells, whole skin and transformed keratinocytes. Candidate genes will be screened for mutations by SSCP and direct sequencing, although a first screen will include hybridization to Southern and northern blots of linked affecteds. Once a candidate mutation is detected unaffected individuals from the same population from the same population will be screened for the same mutation to ensure that it is not a polymorphism that is unrelated to disease state. This putative psoriasis susceptibility gene will then be analyzed in 100-200 sporadic patients with psoriasis and in patients with psoriatic arthritis.
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