Molecular analysis of TSK mouseas a model of scleroderma

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A mouse model of human progressive systemic scleroderma, TSK mice, develop scleroderma and pulmonary emphysema. We have succeeded in identify a mutated form of fibrillin 1 gene, which encodes a intrageneic duplication form. We demonstrated that this mutated form of fibrillin 1 was secreted in culture supernatant of COS7 cells by transient transfection assay. To examine whether this mutated form of fibrillin 1 causes the phenotype of scleroderma, transgenic mice of it under chicken β-actin promoter were generated. The mice developed the thickness of skin along with increased content of hydroxyproline as they aged but not emphysema. And they had autoantibododies for topoisomerase I but not for fibrillin. In addition, wild type mice, which was immunized with expression vector containing the mutated fibrillin 1 as a DNA vaccination method, also developed transient skin thickness with increased hydroxyproline content and autoantibodies for fibrillin. This method did not induce emphysema either. Taken all together, it was concluded that the mutated fibrillin 1 is a causative gene for parts of the phenotypes observed in TSK mice. There are two possibilities for the reason why the emphysema was not caused by this mutated fibrillin 1. First, expression level of the mutated fibrillin 1 was not sufficient for the manifestation of emphysema. Second, there was another responsible gene or genes very close to the mutated fibrillin 1. To test these possibility, another transgenic mice are being generated under keratin 14 promoter or elongation factor promoter.