Genetic Defect of Fibrillin and Scleroderma

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Tight skin (TSK) is an autosomal dominant mutation in mice characterized by excessive accumulation of type I and III collagens and glycosaminoglycans in the skin and various internal organs. The TSK mouse represents an animal model for human scleroderma because it has similar involvement of the skin and is associated with autoimmune phenomena. Recently, the TSK syndrome has been linked to a partial duplication of fibrillin-1 gene predicted to encode a 418kD polypeptide containing 948 amino acids in addition to 312kD normal protein. However, there is no formal demonstration that TSK mutation is similar to fibrillin-1 (Fbn-1) mutation. Fibrillins are constitutes of microfibrils. The production of microfibrils is increased and their structure is altered in scleroderma and TSK mouse. Ongoing studies carried out in the laboratory showed a high incidence of anti Fbn-1 autoantibodies in TSK/+ mice and in Choctaw Indian tribe compared to normal mice or healthy Choctaw individuals. The specific aims of the proposal are: 1. To study whether Tg mice expressing duplicated Fbn-1 gene exhibit the TSK syndrome and whether the fibroblasts express a stable fibrogenic phenotype and to determine whether injection of naked DNA expressing mutated Fbn-1 gene causes local sclerosis. 2. The preparation of characterization of Fbn-1 or elastin specific T cell clones and to study their effects on the production of extracellular matrix proteins by fibroblasts. 3. To study the presence of anti-Fbn-1 autoantibodies in Ssc and other kindred connective tissue diseases.