In inherited prion disease, important information has accrued about which variants are completely penetrant, partially penetrant or simply benign polymorphisms (Figure 2). PTC124 research buy Several publications originate from groups that routinely sequence PRNP and include the distributions of inherited prion disease and new mutations from the UK, China, Japan, US, the Netherlands, and further lessons on how easily inherited prion disease, particularly that caused by truncation mutation,
can be mistaken for Alzheimer’s disease [ 10•, 11, 12, 13, 14, 15, 16, 17 and 18]. Sequencing the CEPH Human Diversity Panel and the Pakistani population showed that small insertions in the octapeptide repeat region of PRNP are probably not pathogenic as they are found in the healthy population, albeit rarely [ 10•, 13 and 19]. Sequencing of the healthy Korean population showed both the M232R and V180I variants implying that these may not be pathogenic mutations [ 11]. Finally, a study of the rare four octapeptide repeat mutation showed that penetrance of the clinical disease is determined by the genotype at codon 129. When the mutation
is linked to codon 129 methionine and the non-mutant allele is also 129 methionine, the disease appears to be penetrant, whereas it is non-penetrant when the non-mutant allele is 129 valine [ 20]. Human genetic studies provide the most direct link between susceptibility genes and patients, however, these are limited in power and inference regarding DZNeP molecular weight mechanisms may
be complex. Uniquely amongst neurodegenerative diseases mice are naturally susceptible to prion diseases thus providing an ideal model organism for both gene discovery and hypothesis testing. Previous mouse quantitative trait loci (QTL) mapping studies using simple crosses have successfully Urease identified many loci linked to prion disease incubation time [21, 22, 23, 24 and 25]. A new report has added to these data using recombinant inbred lines . Many regions are implicated although only loci on Mmu11 are replicated between the experimental models. Large regions of this chromosome have also been implicated in previous studies [ 21, 22 and 23]. The main disadvantage of these studies is the limited resolution resulting in linkage to very large regions that have proved intractable for candidate gene identification. The availability of advanced crosses such as heterogeneous stocks (HS) of mice and the development of the new Collaborative Cross provide ×10–20 higher resolution and are already providing realistic prospects for identifying individual candidate genes [ 27, 28 and 29]. The Northport HS was successfully used to fine map and identify candidate genes on Mmu19 (Hectd2) and Mmu15 (Cpne8) [ 30 and 31••]. For Mmu15, the region of linkage was reduced to 3.6Mb from the previous report of 30Mb [ 24]. Haplotype analysis and genotyping representative SNPs identified Cpne8 as the most promising candidate.