MUTATION OF THE PRION PROTEIN GENE AT CODON-208 IN FAMILIAL CREUTZFELDT-JAKOB-DISEASE

Four point mutations and one insertion within the prion protein (PrP) gene have been tightly linked to the development of inherited prion di sease. We developed a denaturing gradient gel electrophoresis system t hat allowed us to screen the entire open reading frame of the PrP gene . Using this system, we found a new mutation of the PrP gene in a pati ent with pathologically confirmed Creutzfeldt-Jakob disease and a nega tive family history for dementia. DNA sequencing revealed an adenine s ubstitution for guanine at the second position of codon 208, which res ults in the nonconservative substitution of histidine for arginine. Th e same PrP mutation was identified in another younger member of the pe digree but was not present in more than 200 alleles tested. Such findi ngs suggest that the frequency of inherited prion disease might be hig her than ascertained by clinical history alone.