Other mutations result in polymorphic variation, ie, a change which is not associated with disease. Over 25 mutations of the PRNP gene are known and these are listed in Table 2.2 below. It is not yet clear how these subtle changes in the prion protein lead to disease. Sufficient PrP Sc may be generated to lead to disease. As the mutation starts in somatic cells and not germ cells, it is not transmitted to offspring.
Somatic mutations are well-known causes of other diseases including cancer.
In this respect, the origin of sporadic CJD from somatic mutation remains just a very likely hypothesis. This has been interpreted as the consequence of other host genes which modify the expression of PrP Sc . Other mutations are affected by the codon 129 genotype, namely Pro-Leu 102 and the 4 octapeptide repeat insertional mutation. The pathogenicity of the codon 102 mutation was demonstrated experimentally in 1990, when transgenic mice over-expressing the prion protein with an analogous mutation were shown to develop spongiform degeneration spontaneously. In this study, the mutant gene was introduced into fertilised mouse eggs, with the result that many copies integrated into the mouse genome.