MOLECULAR BASIS OF DARIER'S DISEASE

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Darier's disease (DD) is an autosomal doniinant genetic disorder resulting in a disordered abnormally keratinizing epidermis. The research plan is to identify the basic defect in DD by emphasizing gene linkage analysis and studies of DD keratinocytes transplanted to nude mice or cultured in skin equivalents. The avaflability of several large pedigrees, candidate genes and other genetic probes enhance the likelihood of the success of such an approach. The disease is particularly intriguing since it has hyperkeratosis suggesting abnormalities of intracellular maturation and clefting and cell separation suggesting cell surface or cell membrane related abnormalities. The role of environmental factors such as mechanical trauma and sunlight in precipitating the disorder suggest thit the disordered molecular may not be a known structural component of the epidemiis and that a gene exclusion approach to define the primary defect should be pursued. Detailed Aims include: 1) Identification of the gene(s) whose mutation(s) are responsible for DD. Using DNA from members of several large already-identified kindreds with DD and we will assess linkage of the DD gene to candidate genes selected on the basis of the clinical and histologic characteristics of the epidermal abnormalities. Should we find only data excluding these genes, we will embark on a genome-wide search for the DD gene using probes recognizing polymorphic loci throughout the genome for genetic linkage and then physical techniques necessary to "close in" on the DD gene. 2) Determination of the number of independent DD mutations to ascertain whether there are more than one DD locus. Determining the range of DD gene mutations, will enable assessment of structure-function relationships better the normal gene product and the DD product(s). 3) Proving that the basic pathophysiological defect in DD resides in the epidemiis by transplantation studies in nude mice and skin equivalents. Determination of the pathophysiological defects in the behavior of keratinocytes cultured from DD patients to address why phenotypic abnormalities are of late onset and subject to environmental influence such as seasonal changes and ultraviolet B sensitivity. Defining DD on both the genetic and physiological levels will yield new understanding of the defects which should lead to new therapeutic modalities for treating DD.