Seventeen different germline mutations in the PRNP gene on chromosome 20p have been identified in patients with familial Creutzfeldt-Jakob disease (CJD). Of these, an independent mutation (a 48-bp insertion) was discovered and a corresponding phenotype described, and two other complex pathogenic alleles causing fatal familial insomnia were characterized within the last 12 months. A polymorphism at codon 129 was shown to control the age of onset and severity of illness in familial CJD cases and to regulate susceptibility in sporadic and iatrogenic CJD. The codon 129 polymorphism in the PRNP gene does not influence phenotypic expression of other neurologic disorders. Similarly, a polymorphism in the apolipoprotein E gene on chromosome 19 that has been shown to genetically control the age of onset in sporadic Alzheimer's disease, does not influence the age of onset or the rate of progression in CJD. Synthetic peptides that included mutant amino acids at positions 178 and 200 form abundant amyloid fibrils with a tendency to aggregate into large amyloid complexes. In addition, the mutant peptides accelerate fibrillogenesis by the peptides with wild type sequences. These findings are consistent with the hypothesis that specific mutations may alter the folding of the normal host protein to favor formation of insoluble and protease resistant amyloid fibrils.
