PrP genotype (Prnp = PrP gene - chromosome 20 humans, 2 mice)

• DNA sequence of individuals vary each variance is a different genotype
  • each individual contains 2 genes for PrP they may or may not be identical
  • the combination of genes present for each individual defines a genotype
    • having 2 identical genes = homozygous (homozygosity)
    • having 2 different genes = heterozygous (heterozygosity)
    • differences in genes = polymorphisms
    • cloned or highly inbred mice have have identical copies of all genes including PrP = isogenic animals
• changes in the DNA sequence encode slightly different forms of PrP which may or may not be associated with TSE
  • several different PrP sequences of the human PrP gene encode for the various forms of familial TSE
    • alterations in the PrP sequence changes its secondary structure and sensitivity to proteolysis
  • M129 or V129 (methionine or valine at postition 129 in the human PrP) is an example of differences in PrP sequences encoded by Prnp that do not cause a TSE but -
    • M129 with D178N causes fatal famalial insomnia (FFI)
    • V129 with D178N causes familial CJD (fCJD)
    • although seemingly similar, the clinical symptoms of FFI and fCJD are quite different
    • also, infection of isogenic mice with FFI or fCJD results in different clinical expressions
• differences in the genotype of infected animals will affect clinical outcome; phenotype (thus isogenic animal must be used to compare strains of TSE
  • difference in genotype of infected animals of sheep led to the identification of numerous strains of Scrapie of which many probably resulted from only a few Scrapie strains but the phenotype differered dependent on the sheep genotype
• although initial genotype can effect the strain of TSE (ex. FFI and fCJD), once the mis-folding of PrP^C forms, passaging the TSE through varying genotypes does not necessarily change the TSE strain (i.e. fidelity of TSE)

• there are several human PrP genotypes including point mutations, octarepeat inserts and stop codons
• cattle do not have PrP polymorphisms other than the presence or absence of an additional octarepeat (five or six present)
  • the presence or lack of the addtional octarepeat does not appear to influence susceptibility to BSE
• there are several sheep PrP genotypes

Sinc = Prnp = Prn-i