Intrachromosomal deletions linking Dpl expression to the PrP promoter produce cerebellar degeneration that can be abrogated by the introduction of wild-type PrP transgenes. Since Dpl-like truncated forms of PrP are neuropathogenic in mice and likewise counterbalanced by expression of PrP(C) we asked whether naturally occurring mutant forms of human PrP have Dpl-like attributes. Five PRNP missense mutations causing familial Creutzfeldt-Jakob disease (F-CJD) map to a helical region found in both PrP(C) and Dpl and result in amino acids identical to conserved residues in Dpl. These F-CJD alleles may cause mutant PrP to become a weak mimetic of Dpl structure and/or function.