DEFECTIVE COPPER-BINDING TO APO-CERULOPLASMIN IN A RAT MODEL AND PATIENTS WITH WILSONS-DISEASE

To examine the mechanism of decrease in serum ceruloplasmin (Cp) in Lo ng-Evans Cinnamon (LEC) rats, a proposed model of Wilson's disease, we analyzed Cp products at the stages of transcription and translation. Northern blot analysis and immunoblot analysis showed that the level a nd the molecular size of Cp mRNA and protein in LEC rats were similar to those in control Long-Evans-Agouti (LEA) rats. However, the ferroxi dase activity of Cp was significantly decreased in LEC rats. We separa ted serum Cp into two forms by native polyacrylamide gel electrophores is with pH modification: one was a holo-Cp with copper and ferroxidase activity, and the other was an inactive apo-Cp without copper. Holo-C p was the predominant form in LEA rats and normal humans, whereas apo- Cp was the major form in LEC rats and patients with Wilson's disease. The cosegregation of apo-Cp predominance with the disease in LEC rats was analyzed using backcross rats. Apo-Cp was dominant in 8 of 11 offs pring with disease but in none of 19 normal offspring. These results i ndicate that a genetic disturbance of copper binding to apo-Cp may be closely associated with the pathogenesis in LEC rats, and probably in Wilson's disease.