In the present experiments, we observed transmission of 1 new familial prion disease-associated mutation, Y226X, after injection of human patient brain tissue into tg66 transgenic mice overexpressing human PrP. Transmission was indicated by detection of PrPSc deposits, typical prion spongiform degeneration and gliosis in brains of recipient mice, detection of PrPSc by immunoblot and PrP amyloid seeding activity by RT-QuIC assay in 4 of 8 tg66 recipients. To confirm these data a second passage in tg66 mice has been started and one first passage Y226X tg66 brain which was positive in the other tests has already caused clinical disease in 9/9 mice in the second pass from 167 to 185 dpi, thus confirming the first passage transmission results. Transmission from Y226X patient brain is the first example of transmission from a human patient with a mutation involving truncation of PrP. No transmission was observed in previous attempts using Y145X or Y163X brain tissues [27, 44]. and in the present work, we also saw no transmission using brain from a Q227X patient.