title: PRNP contains both intronic and upstream regulatory regions that may influence susceptibility to Creutzfeldt-Jakob Disease.
abstract: The Prion protein (PrP) plays a central role in Creutzfeldt-Jakob Disease (CJD) and other transmissible spongiform encephalopathies (TSEs). Mutations in the protein coding region of the human PrP gene (PRNP), which have been proposed to alter the stability of the PrP protein, have been linked to a number of forms of TSE. However, the majority of CJD cases are not associated with mutations in the PRNP coding region and alternative mechanisms must therefore underlie susceptibility to these forms of CJD. Transgenic mice, that over- or under-express PrP genes, have shown a correlation between the level of PrP gene expression and the incubation time of disease. Polymorphisms that lead to alterations in human PRNP gene expression, could therefore be candidates for influencing susceptibility of an individual to CJD. In order to investigate this hypothesis, we have defined an upstream and intronic regulatory region of the PRNP gene. Sequencing of these regions in controls, sporadic CJD (sCJD) and variant CJD (vCJD) patients has identified three polymorphisms, all of which are more common in sCJD patients than controls. Our data suggests that polymorphisms in the regulatory region of the PRNP gene may be a risk factor for CJD.
authors.affiliation: Neuropathogenesis Unit, Institute for Animal Health, West Mains Road, Edinburgh EH9 3JF, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: McCormack
authors.forename: Herbert N
authors.initials: HN
authors.lastname: Baybutt
authors.forename: Dawn
authors.initials: D
authors.lastname: Everington
authors.forename: Robert G
authors.initials: RG
authors.lastname: Will
authors.forename: James W
authors.initials: JW
authors.lastname: Ironside
authors.forename: Jean C
authors.initials: JC
authors.lastname: Manson
mesh_terms: D001483:Base Sequence; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics*; D004247:DNA / Q000737:chemistry / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011328:Prions / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D011328:Prions; D011993:Recombinant Fusion Proteins; D004247:DNA; D015500:Chloramphenicol O-Acetyltransferase