Frequent Missense and InsertionDeletion Polymorphisms in the Ovine Shadoo Gene Parallel Species-Specific Variation in PrP 英文参考文献.docVIP

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Frequent Missense and InsertionDeletion Polymorphisms in the Ovine Shadoo Gene Parallel Species-Specific Variation in PrP 英文参考文献.doc

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Frequent Missense and InsertionDeletion Polymorphisms in the Ovine Shadoo Gene Parallel Species-Specific Variation in PrP 英文参考文献

FrequentMissenseandInsertion/Deletion PolymorphismsintheOvineShadooGeneParallel Species-SpecificVariationinPrP NathalieDaude1,SereneWohlgemuth1,EkaterinaRogaeva2,A.HosseinFarid3,MikeHeaton4 ,David Westaway1* 1CentreforPrionsandProteinFoldingDiseases,UniversityofAlberta,Edmonton,Alberta,Canada,2CentreforResearchinNeurodegenerativeDiseases,Universityof Toronto, Toronto, Ontario, Canada, 3Department of Animal Science, Nova Scotia Agricultural College, Truro, Nova Scotia, Canada, 4United States Department of Agriculture,U.S.MeatAnimalResearchCenter,ClayCenter,Nebraska,UnitedStatesofAmerica Abstract Background:ThecellularprionproteinPrPCisencodedbythePrnpgene.Thisproteinisexpressedinthecentralnervous system (CNS) and serves as a precursor to the misfolded PrPSc isoform in prion diseases. The prototype prion disease is scrapie in sheep, and whereas Prnp exhibits common missense polymorphisms for V136A, R154H and Q171R in ovine populations,geneticvariationinmousePrnpislimited.RecentlytheCNSglycoproteinShadoo(Sho)hasbeenshownto resemblePrPCbothinacentralhydrophobicdomainandinactivityinatoxicityassayperformedincerebellarneurons.Sho proteinlevelsarereducedinprioninfectionsinrodents.PromptedbythesepropertiesoftheShoproteinweinvestigated theextentofnaturalvariationinSPRN. Principal Findings:Paralleling thecasefor ovineversushuman andmurine PRNP,wefailedtodetectsignificantcoding polymorphismsthatalterthematureShoproteininasampleofneurologicallynormalhumans,orindiversestrainsofmice. However,ovineSPRNexhibited4missensemutationsandexpansion/contractioninaseriesof5tandemAla/Gly-containing repeats R1-R5 encoding Sho’s hydrophobic domain. A Val71Ala polymorphism and polymorphic expansion of wt 67(Ala)3Gly70 to 67(Ala)5Gly72 reached frequencies of 20%, with other alleles including D67–70 and a 67(Ala)6Gly73 expansion. Sheep V71, A71, D67–70 and 67(Ala)6Gly73 SPRN alleles encoded proteins with similar stability and posttranslationalprocessingintransfectedneuroblastomacells. Signific