Genetic approach to Wilson disease by use of the hereditary hepatitis LEC rats

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LEC rats develop abruptly about 4months after birth. Abot 30% of the rats die of fulminant hepatitis within 1 week, and remainder survive with chronic hepatitis and subsequently develop liver cancer. Recently, high levels of copper accumulation in the livers of LEC rats and gross reduction of serum ceruloplasmin have been found. These clinical and biochemical characteristics of LEC rats are very similar to Wilson disease, and therefore, we proposed the LEC as an animal model for Wilson disease. We defined hts as the gene symbol for the hepatitis. In this research project, we have examined whether the gene, WNE, for Wilson disease is homologous to the hts by use of backcross rats :(1) Genetic analysis by use of backcross rats of LEC showed no linkage between hts and genes for ESD, RB1, and several minisatellite DNAs which linked to the WND in human, indicating that the hts locates on a different chromosome from no.15 on which RB1 and ESD are located.(2) As gross reductin of serum ceruloplasmin was found in LEC rats, we have isolated the gene for ceruloplasmin from the LEC, and found no mutation in the gene of LEC, suggesting that the copper accumulatino is not due to alteration of the ceruloplasmin gene.Linkage analysis of the hts and WND for Wilson disease showed the identical segregation pattern and no recombination demonstrating that the WND gene is a prime candidate for hts.Thus, the results obtained here suggest that the hepatitis of LEC rats may be caused by a defect in a copper transporting ATPase, possibly due to mutation of hts.