The long-term goal of this study is to understand the molecular mechanisms of neoformation of dermal tissue in fibrotic diseases. To achieve this goal we began to study hereditary keloid formation. Keloids are benign tumors of the skin or cornea caused by clonal overactivity of fibroblasts during abnormal wound repair. The relatively large number of familial cases of keloid formation makes it possible to propose a genetic approach for the identification of a gene responsible for increased cell proliferation and extracellular matrix expression. We performed linkage analysis of one large family afflicted with an autosomal dominant form of hereditary keloid formation to identify the chromosomal locus of the disease gene by using polymorphic microsatellite markers covering the entire genome. We have identified a possible disease gene locus and are now in the process of establishing a high resolution map of the keloid locus by including other pedigrees that show locus homogeneity. Ideally, the interval will be restricted to less than 1-2 cM. The keloid gene will be identified by candidate gene cloning, positional candidate gene cloning, or positional cloning. We will construct a physical map of the keloid locus using YAC and cosmid clones covering this interval. Once the disease gene has been identified by mutation analysis and by co-segregation with the affected phenotype, studies are planned to characterize the protein product and its interactions with other genes or gene products. Depending on the nature of the keloid gene, we will plan in vitro studies of fibroblast and organ cultures as well as a mouse model that expresses the mutated gene by homologous recombination (knock-in). These studies should enable us to perform further studies on down-stream events, which are involved in the fibrosis of keloid scars. Identifying and characterizing the keloid gene product, and identifying other proteins or genes with which it interacts, will help us understand abnormal fibroblast regulation. We suggest that keloids are an excellent model for studying regulation of fibroblast activation and extracellular matrix expression during wound healing and fibrosis.
