Linkage disequilibrium in the chromosomal region surrounding the prion protein gene (Prnp) in Norwegian dairy goat

The Norwegian dairy goat is the only known mammal that naturally lacks cellular prion protein (PrPC); this due to a nonsense mutation in the prion protein gene (PRNP). This makes the goats interesting model animals in studies of the physiological functions of the cellular prion protein. Because the PRNP gene is both a highly expressed and highly conserved gene, and therefore believed to be an important gene, it is hypothesized that the mutation in the Norwegian dairy goats is a fairly new mutation, and thus have a relatively high amount of homozygosity in the chromosomal region around the mutation. In this master thesis, I have particularly been investigating the extent of linkage disequilibrium in the region surrounding the prion protein gene (PRNP) in the Norwegian dairy goat by. To estimate the length of the haplotype surrounding PRNPter variant, the SNPallele frequencies were tested in animals homozygous for this variant, and compared to the corresponding SNP-allele frequencies in heterozygous goats and a control group of unrelated goats without the mutation. Runs of homozygosity (ROH) were also calculated for the complete chromosome 13 to compare the PRNP-region to the rest of the chromosome. The results showed a distinct decrease in the wild type alleles in the area surrounding the PRNP gene in the goats with the PRNPter/ter genotype, which none of the other groups of goats showed. The goats homozygous for the mutation also showed some runs of homozygosity (ROH) surrounding the gene that the goats with PRNP does not have; although the length of the runs were short compared to other parts of chromosome 13. Overall, the results showed that the goats might be suitable as model animals, and that the mutated PRNP variant reside in a haplotype with a minimum length of around 2.6 MB. However, this is a gene dense region, which is important to consider if the goats with the PRNPter variant are to be used as model animals on possible phenotypic effects of the PRNP gene.Norsk melkegeit er det eneste kjente pattedyret som naturlig mangler cellulært prion protein (PrPC); dette på grunn av en nonsense mutasjon i prionproteingenet (PRNP). Dette kan gjøre geitene til interessante modelldyr i studier av de fysiologiske egenskapene til det cellulære prionproteinet; men fordi PRNP-genet både er sterkt uttrykt og er et sterkt konservert gen, er en hypotese at mutasjonen i den norske melkegeita er en ganske ny mutasjon, og at det derfor er relativt mye homozygoti i kromosomområdet rundt mutasjonen. I denne masteroppgaven har jeg spesielt undersøkt utbredelsen av koblingsulikevekt i området rundt PRNP på kromosom 13 i norsk melkegeit. For å beregne lengden på haplotypen som PRNPter varianten er en del av, ble SNP-allelfrekvenser i dette området testet hos geiter som er homozygote for varianten, og deretter sammenlignet med tilsvarende frekvenser hos heterozygote geiter, og en kontrollgruppe ubeslektede geiter uten mutasjonen. «Runs of homozygosity» (ROH) ble også analysert for hele kromosom 13 for å sammenligne PRNP-området med resten av kromosomet. Resultatene viste en tydelig nedgang i villtypealleler i området rundt PRNP-genet i geitene med PRNPter/ter genotypen, noe ingen av de andre gruppene av geiter viste. Geitene som er homozygote for den muterte genvarianten viste også noe runs of homozygosity (ROH - lange rekker med homozygote områder) i området rundt genet som de resterende geitene mangler; på tross av at de homozygote områdene var korte sammenlignet med andre områder på kromosom 13. Alt tatt i betraktning viser resultatene at geitene kan være gode modelldyr, og også at mutasjonen ligger i en haplotype med en minimumslengde på ca 2.6 MB. Dette er dog et område med stor gentetthet, noe som må tas hensyn til dersom man skal benytte geitene med PRNPter varianten som modelldyr for å undersøke PRNP-genets mulige fenotypiske effekter.M-BIOTE

Demyelinating polyneuropathy in goats lacking prion protein.

Studies in mice with ablation of Prnp, the gene that encodes the cellular prion protein (PrPC), have led to the hypothesis that PrPC is important for peripheral nerve myelin maintenance. Here, we have used a nontransgenic animal model to put this idea to the test; namely, goats that, due to a naturally occurring nonsense mutation, lack PrPC . Teased nerve fiber preparation revealed a demyelinating pathology in goats without PrPC . Affected nerves were invaded by macrophages and T cells and displayed vacu- olated fibers, shrunken axons, and onion bulbs. Peripheral nerve lipid composition was similar in young goats with or without PrPC , but markedly different between cor- responding groups of adult goats, reflecting the progressive nature of the neuropathy. This is the first report of a subclinical demyelinating polyneuropathy caused by loss of PrPC function in a nontransgenic mammal.publishedVersio

Demyelinating polyneuropathy in goats lacking prion protein

Studies in mice with ablation of Prnp, the gene that encodes the cellular prion protein (PrPC), have led to the hypothesis that PrPC is important for peripheral nerve myelin maintenance. Here, we have used a nontransgenic animal model to put this idea to the test; namely, goats that, due to a naturally occurring nonsense mutation, lack PrPC. Teased nerve fiber preparation revealed a demyelinating pathology in goats without PrPC. Affected nerves were invaded by macrophages and T cells and displayed vacuolated fibers, shrunken axons, and onion bulbs. Peripheral nerve lipid composition was similar in young goats with or without PrPC, but markedly different between corresponding groups of adult goats, reflecting the progressive nature of the neuropathy. This is the first report of a subclinical demyelinating polyneuropathy caused by loss of PrPC function in a nontransgenic mammal

Demyelinating polyneuropathy in goats lacking prion protein.

Studies in mice with ablation of Prnp, the gene that encodes the cellular prion protein (PrPC), have led to the hypothesis that PrPC is important for peripheral nerve myelin maintenance. Here, we have used a nontransgenic animal model to put this idea to the test; namely, goats that, due to a naturally occurring nonsense mutation, lack PrPC . Teased nerve fiber preparation revealed a demyelinating pathology in goats without PrPC . Affected nerves were invaded by macrophages and T cells and displayed vacu- olated fibers, shrunken axons, and onion bulbs. Peripheral nerve lipid composition was similar in young goats with or without PrPC , but markedly different between cor- responding groups of adult goats, reflecting the progressive nature of the neuropathy. This is the first report of a subclinical demyelinating polyneuropathy caused by loss of PrPC function in a nontransgenic mammal