The genetic/molecular basis of a variety of skin disorders, and other selected hereditary disorders of interest, is studied with the goal being to identify the gene(s) involved. Both gene localization methods (linkage analysis) and a wide variety of mutation detection assays are used. Subsequent goals are to correlate the molecular findings with the clinical presentation of the disorder to better understand the structure/function relationship of the gene expression in human tissues. In the past year we have made progress in developing a human to mouse skin graft model of lamellar ichthyosis for use in testing transglutaminase enzyme replacement therapy in this disease. We have identified mutations in the PTCH gene (the human homolog of Drosophila patched) 37 individuals from 10 families with basal cell nevus syndrome and are currently analyzing extensive clinical data on these individuals for genotype/phenotype correlations. The genomic organization of the FALDH gene, mutations in which we showed are responsible for the autosomal recessive disorder Sjogren-Larsson Syndrome) has been determined, and differential tissue expression analyzed. We have continued to fine map the gene for erythrokeratodermia variabilis and now have a candidate region of 2.6cM. Mutation screens of candidate genes in this region are being pursued. We have evaluated two large families with ichthyosis vulgaris and identified a possible histologic variable which may assist in diagnosis of this highly heterogeneous disorder. Preliminary linkage analysis of candidate regions has been promising and candidate genes are being sequenced to search for mutations. A complete genome screen using pooled DNA samples from affected, unaffected relatives, and controls is being pursued to identify the gene for the rare, autosomal recessive disorder Kuskokwim syndrome. This congenital arthrogyposis is found only in the Yupik Eskimos. Seventy-five percent of the genome has thus far been excluded. Fifty individuals with severe cystic acne, treated at the NIH in the 1970's and 1980's have been contacted and family pedigrees are being collected to test for genetic factors using the statistical technique of segregation analysis.
