The transmissible agent detected in human patients with Y226X PrP and possibly also with G131V PrP is likely to contain aggregates of the mutant PrP expressed in these patients. However, both these patients, similar to most known familial prion disease patients, are heterozygous for the mutant PrP allele, and thus they express both normal and mutant PrP. Presence of the non-mutant PrP isoform has been associated with insoluble aggregates of mutant PrP in some patients with familial prion diseases [7, 14, 41, 46]. Thus, it is possible that the normal and mutant PrP isoforms present in familial prion disease patients may both contribute to the disease pathogenesis and/or generation of a transmissible agent. Similarly, we have previously described the influence of co-expressed normal and mutant PrP alleles (expressing anchorless PrP) in scrapie-infected transgenic mice resulting in deposits of both nonamyloid and amyloid PrPSc as well as more rapid disease progression .