NR AUSC
AU Grubenbecher,S.; Stüve,O.; Hefter,H.; Korth,C.
TI Prion protein gene codon 129 polymorphism modulates the clinical course of neurological Wilson disease
QU TSE-Forum, 6. Kongress - Nationale TSE-Forschungsplattform, Greifswald 26.6.-28.6.2006, Poster: Pathogenese/Infektion PATH-03
PT Konferenz-Poster
AB
Wilson Disease (WD) is an autosomal recessive disorder of copper metabolism, characterized by toxic copper accumulation mainly in liver and brain. Although the affected gene, ATP7B, a copper transporting P-type ATPase has been cloned, clear genotype-phenotype relationships could not be established suggesting an influence of other genes. Since the cellular prion protein (PrPc) is known to bind copper under physiological conditions, we hypothesized that PrP could play a role in copper metabolism in vivo and be a genetic modifier of neurological WD.
Homozygosity at codon 129 (methionine or valine) of the prion protein gene (PRNP) influences susceptibility to Creutzfeldt Jakob disease. Recently, PRNP was also shown to influence non prion-related diseases like early onset Alzheimer's disease, cognitive abilities during aging, and long-term memory function in healthy volunteers. These data suggest a broader role of normal PrP in neuronal functions.
In this context we sequenced PRNP isolated from whole blood samples of patients with clinical WD and investigated the influence of the PRNP polymorphism at codon 129 (and possible other mutations) on clinical of these patients in a blinded fashion.
We could show that in our WD patient group allele frequencies were not different from those of a healthy German control population and that PRNP codon 129 genotypes did not result in different serum copper, serum ceruloplasmin, or copper in 24 hour urine concentrations. However, PRNP codon 129 methionine homozygosity led to significantly more severe neurological symptoms in elderly patients, particularly tremor, supporting the notion that PRNP codon 129 homozygosity contributes to neuronal vulnerability.
AD Stephanie Grubenbecher (grubenbecher@uni-duesseldorf.de), Carsten Korth, Institute for Neuropathology, Heinrich Heine University of Düsseldorf, 40225 Düsseldorf, Germany; Olaf Stüve, Department of Neurology, University of Texas Southwestern Medical School, Dallas, TX 75390; Olaf Stüve, Neurology Section, VA North Texas Health Care System, Medical Service; Harald Hefter, Department of Neurology, Heinrich Heine University of Düsseldorf, 40225 Düsseldorf, Germany
SP englisch
PO Deutschland
OR Tagungsband