Chronic liver disease is a documented clinical problem in about 10% of CF patients and is the second leading cause of death. Since there is not predictable correlation between the CF gene defect and the presence or absence of liver disease, other genetic factors are clearly modifying the disease pathogenesis in this organ. In our laboratories we have bred a knockout mouse, BcCftr/m1UNC/m1UNC, with develops liver disease starting in infancy. These animals represent the first reported knockout mouse with a liver lesion. No liver lesions were observed in two other lines of mice bearing the identical gene knockout room. Interestingly the BcCftr/m1UNC/m1UNC animals had no lung phenotype but appeared to share the same severe gastrointestinal problems experienced by these other two strains. Wild type littermates of all three lines were predictably free of liver disease. This mouse presents with a unique opportunity to study, not only the genetic modifiers affecting expression of the phenotype but enables to examine some of the biochemical pathways which be involved in the pathogenesis of the disease. Preliminary examination of the phenotype of this animal has identified a catalase deficiency in the livers of these animals and this was associated to a total absence of peroxisomes. The catalase deficiency will be used as a marker enzyme for the location of the modifier gene by cross breeding strains (Rozmahel portion of the pilot). Although not identical to the focal cholestasis lesions of human CF liver disease, the appearance of lesions are limited with no CFTR and represent a pathological consequence of its deficiency. We will attempt to identify some of these defective pathways in this pilot study.
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