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Functional relevance of DNA polymorphisms within the promoter region of the prion protein gene and their association to BSE infection

Kseniya Kashkevich^*, Andreas Humeny^*, Ute Ziegler, Martin H. Groschup, Petra Nicken^,1, Tosso Leeb^,2, Christine Fischer, Cord-Michael Becker^* and Katrin Schiebel^*,3

^* Institute for Biochemistry, Emil-Fischer-Center, University of Erlangen-Nürnberg, Erlangen, Germany;

Friedrich-Loeffler-Institut, Institute for Novel and Emerging Infectious Diseases, Insel Riems, Germany;

Institute for Animal Breeding and Genetics, University of Veterinary Medicine, Hannover, Germany; and

Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany

³Correspondence: Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen-Nürnberg, Fahrstrasse 17, D-91054 Erlangen, Germany. E-mail: katrin.schiebel{at}biochem.uni-erlangen.de

Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases that can occur spontaneously or can be caused by infection or mutations within the prion protein gene PRNP. Nonsynonymous DNA polymorphisms within the PRNP gene have been shown to influence susceptibility/resistance to infection in sheep and humans. Analysis of DNA polymorphisms within the core promoter region of the PRNP gene in four major German bovine breeds resulted in the identification of both SNPs and insertion/deletion (indel) polymorphisms. Comparative genotyping of both controls and animals that tested positive for bovine spongiform encephalopathy (BSE) revealed a significantly different distribution of two indel polymorphisms and two SNPs within Braunvieh animals, suggesting an association of these polymorphisms with BSE susceptibility. The functional relevance of these polymorphisms was analyzed using reporter gene constructs in neuronal cells. A specific haplotype near exon 1 was identified that exhibited a significantly lower expression level. Genotyping of nine polymorphisms within the promoter region and haplotype calculation revealed that the haplotype associated with the lowest expression level was underrepresented in the BSE group of all breeds compared to control animals, indicating a correlation of reduced PRNP expression and increased resistance to BSE.—Kashkevich, K., Humeny, A., Ziegler, U., Groschup, M. H., Nicken, P., Leeb, T., Fischer, C., Becker, C.-M., Schiebel, K. Functional relevance of DNA polymorphisms within the promoter region of the prion protein gene and their association to BSE infection.

Key Words: PRNP • German bovine breeds • haplotype • expression • single nucleotide polymorphism