Genetics of Prion Diseases

Normal cellular prion protein is encoded by a single exon of a single copy gene.

Can a mutated prion gene result in disease without exogenous infection or predispose an individual to exogenous infection?

• Apparently, yes.

There are at least 20 known mutations in the PrP gene sequence resulting in "spontaneous" PrP^sc formation.

• people who are homozygous at the polymorphic amino acid PrP V129 are predisposed to both acquired and sporadic CJD
• people who are homozygous at the polymorphic amino acid PrP M129 are predisposed to BSE
• two families with genetic GSS have the same double mutation (D178N; E200K)
• some GSS families have a P102L mutation

Experimental transmission of BSE to a variety of animals including sheep suggests that susceptibility is not entirely controlled by overall sequence similarity between donor and recipient PrP.

• sheep have a PrP protein variant that differs from bovine PrP at codons 98, 100, 143, 146, 155, 168, 198 and 218
• sheep succumb to experimental BSE challenge in about 500 d (Goldman et al. 1994).
  • This is similar to the time for scrapie transmission in these sheep where no PrP sequence difference exists.
• thus BSE is transmissible to sheep

• sheep homozygous for a PrP gene encoding one additional substitution of arginine for glutamine at codon 171 (R171Q) are entirely resistant to scrapie (Goldmann et al. 1994; Badenhorst. 1978).
• Sheep heterozygous at codon 171 are resistant to both BSE and scrapie for at least 1,800 d after challenge
  • the human sequence contains R171, indicating that this particular residue is not responsible for the inability of scrapie to infect humans

  According to Goldman et al. (1996) the combined effects of six amino acid differences between sheep and bovine PrP proteins appear to be outweighed by a single additional change at codon 171 indicating that this may be a crucial region. While these alterations and relationships are interesting, correlation between any single feature of a PrP protein sequence and likely transmissibility must be demonstrated experimentally.

Collinge et al. (1995) ref unk. suggest aberrant bovine PrP is unlikely to affect normal human PrP. Researchers at the Imperial College School of Medicine studied mice genetically-engineered to produce human prion protein as well as normal mouse prion protein. When injected with CJD the mice fell victim to the disease, demonstrating that with human PrP, the human disease CJD was transmitted. They then exposed similar mice to BSE. Abnormal mouse PrP was formed, but no abnormal human PrP, suggesting the bovine PrP does not interact with the human protein to cause disease. However, the human PrP used for this work was hPrP V129 which appears not to be susceptible to BSE.

These experiments were repeated with genetically-modified mice that express only human PrP and no mouse PrP. These remain well at 500+ days after inoculation (300 days longer than for CJD to develop in mice of this genotype) and are approaching their natural life span of 600-700 days..

Mice with a murine transgene with the P102L GSS mutation spontaneously develop a lethal scrapie-like disease.

"Knock out" mice (mice lacking PrP completely) do not develop overt prion disease (even on challenge) which probably indicates that loss of normal PrP function is not responsible for disease characteristics.