Congenital factor XIII (FXIII) deficiency is a severe bleeding disorder. We previously identified an Arg260Cys missense mutation and an exon-IV deletion in patients' A subunit genes, F13A. To characterize the molecular/cellular basis of this disease, we expressed a wild type and these mutant A subunits in baby hamster kidney (BHK) cells. The mutant proteins were expressed less efficiently than the wild type. These mutants gradually decreased inside BHK cells, whereas the wild type remained largely unchanged. The decline/decrease in these mutants was completely blocked/restored by a potent proteasome inhibitor, MG-132. This was consistent with the prediction by molecular modelling that the mutant molecules would lose the native structure of wild-type molecule, leading to their instability and degeneration and ultimately to degradation. These mutants might have significantly altered conformations, resulting in the rapid degradation by the proteasome inside the synthesizing cells, and ultimately leading to FXIII deficiency.