In the present study, we performed transmission experiments using brain tissue of human patients expressing three previously untested PrP mutations (Y226X, Q227X, and G131V) [22, 23, 30]. Tg66 transgenic mice expressing human PrP at a level 8–16-fold higher than physiological levels [37, 38] were used as recipients. Interestingly, two of these human patients had PrP mutations resulting in a stop codon at positions 226 or 227, thus lacking the final 5–6 amino acid residues of PrP as well as the C-terminal glycophosphatidylinositol (GPI) anchor group. Thus, the mutant PrP in these two patients was remarkably similar to the anchorless PrP expressed in tg44 transgenic mice [8, 10], which showed severe cerebral amyloid angiopathy (CAA) after scrapie infection, similar to the Y226X patient. In this work, we observed transmission to tg66 mice by tissue from the Y226X patient starting at 593 dpi, and possible transmission of G131V starting at 531 dpi. In contrast, no transmission by Q227X was seen by 798 dpi which was the latest time-point analyzed. Y226X is the first human PrP mutant associated with PrP truncation which has been found to be transmissible.