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J. Biol. Chem., Vol. 280, Issue 45, 37408-37414, November 11, 2005

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Bovine Prion Protein Gene (PRNP) Promoter Polymorphisms Modulate PRNP Expression and May Be Responsible for Differences in Bovine Spongiform Encephalopathy Susceptibility^*

Petra Sander, Henning Hamann, Cord Drögemüller, Kseniya Kashkevich, Katrin Schiebel, and Tosso Leeb1

From the Institute for Animal Breeding and Genetics, University of Veterinary Medicine, Bünteweg 17p, 30559 Hannover, Germany and the Institute for Biochemistry, University of Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany

The susceptibility of humans to the variant Creutzfeldt-Jakob disease is greatly influenced by polymorphisms within the human prion protein gene (PRNP). Similar genetic differences exist in sheep, in which PRNP polymorphisms modify the susceptibility to scrapie. However, the known coding polymorphisms within the bovine PRNP gene have little or no effect on bovine spongiform encephalopathy (BSE) susceptibility in cattle. We have recently found a tentative association between PRNP promoter polymorphisms and BSE susceptibility in German cattle (Sander, P., Hamann, H., Pfeiffer, I., Wemheuer, W., Brenig, B., Groschup, M., Ziegler, U., Distl, O., and Leeb, T. (2004) Neurogenetics 5, 19–25). A plausible hypothesis explaining this observation could be that the bovine PRNP promoter polymorphisms cause changes in PRNP expression that might be responsible for differences in BSE incubation time and/or BSE susceptibility. To test this hypothesis, we performed a functional promoter analysis of the different bovine PRNP promoter alleles by reporter gene assays in vitro and by measuring PRNP mRNA levels in calves with different PRNP genotypes in vivo. Two variable sites, a 23-bp insertion/deletion (indel) polymorphism containing a RP58-binding site and a 12-bp indel polymorphism containing an SP1-binding site, were investigated. Band shift assays indicated differences in transcription factor binding to the different alleles at the two polymorphisms. Reporter gene assays demonstrated an interaction between the two postulated transcription factors and lower expression levels of the ins/ins allele compared with the del/del allele. The in vivo data revealed substantial individual variation of PRNP expression in different tissues. In intestinal lymph nodes, expression levels differed between the different PRNP genotypes.

Received for publication, June 10, 2005 , and in revised form, July 20, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant Le1032/10; the Bavarian for Prion Research Initiative; and the German TSE Research Platform, which is cooperatively funded by the German Federal Ministries for Consumer Protection, Nutrition, and Agriculture and for Education and Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3 and Tables 1–3.

¹ Present address and to whom correspondence should be addressed: Institute of Genetics, Bremgartenstr. 109a, 3001 Berne, Switzerland. Tel.: 41-31-631-2326; E-Mail: Tosso.Leeb{at}itz.unibe.ch.

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