The incubation period of scrapie in sheep is controlled by the Sip gene which has two alleles (sA and pA). Following experimental challenge with SSBP/1 scrapie, a short incubation period is conferred by the partially dominant sA allele. Restriction fragment length polymorphisms of the scrapie-associated fibril protein (PrP) gene are associated with the Sip alleles. By sequencing the protein coding region of the PrP gene in Cheviot sheep selected for differing Sip genotypes, we have found four PrP protein variants which differ at three positions: amino acid 112 (Ala/Val), amino acid 130 (Arg/His) and amino acid 147 (Arg/Gln). The Val 112 variant can be distinguished at the DNA level by an RspXI restriction site which is not present in the Ala 112 form. Val 112 appears to be linked to a short incubation period of experimentally induced scrapie in the Cheviot sheep and therefore with the Sip sA allele. These results provide new evidence that the PrP protein may be a product of the Sip locus.
BruceM. E.,
McConnellI.,
FraserH.,
DickinsonA. G.1991; The disease characteristics of different strains of scrapie in Sinc congenic mouse lines: implications for the nature of the agent and host control of pathogenesis. Journal of General Virology 72:595–603
CarlsonG. A.,
GoodmanP. A.,
LovettM.,
TaylorB. A.,
MarshallS. T.,
Peterson-TorchiaM.,
WestawayD.,
PrusinerS. B.1988; Genetics and polymorphism of the mouse prion gene complex; control of scrapie incubation time. Molecular and Cellular Biology 8:5528–5540
CarlsonG. A.,
WestawayD.,
DeArmondS. J.,
Peterson-TorchiaM.,
PrusinerS. B.1989; Primary structure of prion protein may modify scrapie isolate properties. Proceedings of the National Academy of Sciences, U.S.A 86:7475–7479
DickinsonA. G.1976; Scrapie in sheep and goats. In Slow Virus Diseases of Animals and Man pp 209–241 Edited by
KimberlinR. H.
Amsterdam: North-Holland;
DickinsonA. G.,
OutramG. W.1988; Genetic aspects of unconventional virus infections: the basis of the virino hypothesis. In Novel Infectious Agents and The Central Nervous System Ciba Foundation Symposium vol 135 pp 63–83 Edited by
BockJ.,
MarshJ.
London: Wiley-Interscience;
DickinsonA. G.,
StampJ. T.,
RenwickC. C.,
RennieJ. C.1968; Some factors controlling the incidence of scrapie in Cheviot sheep injected with a Cheviot-passaged scrapie agent. Journal of Comparative Pathology 78:313–321
Doh-uraK.,
TateishiJ.,
SasakiH.,
KitamotoT.,
SakakiY.1989; Pro-Leu change at position 102 of prion protein is the most common but not the sole mutation related to Gerstmann-Straussler syndrome. Biochemical and Biophysical Research Communications 163:974–979
EngelkeD. R.,
HoenerP. A.,
CollinsF. S.1988; Direct sequencing of enzymatically amplified human genomic DNA. Proceedings of the National Academy of Science, U.S.A 85:544–548
FosterJ. D.,
HunterN.1991; Partial dominance of the sA allele of the Sip gene in the control of experimental scrapie in Cheviot sheep. Veterinary Record 28:548–549
GoldgaberD.,
GoldfarbL. G.,
BrownP.,
AsherD. M.,
BrownT.,
ScottL.,
TeenerJ. W.,
FeinstoneS. M.,
RubensteinR.,
KascsakR.,
BoellaardJ. W.,
GajdusekD. C.1989; Mutations in familial Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker’s syndrome. Experimental Neurology 106:204–206
GoldmannW.,
HunterN.,
FosterJ. D.,
SalbaumJ. M.,
BeyreutherK.,
HopeJ.1990; Two alleles of a neural protein gene linked to scrapie in sheep. Proceedings of the National Academy of Science, U.S.A 87:2476–2480
GoldmannW.,
HunterN.,
MartinT.,
DawsonM.,
HopeJ.1991; Different forms of the bovine PrP gene have five or six copies of a short, G-C-rich element within the protein-coding exon. Journal of General Virology 72:201–204
HayB.,
BarryR. A.,
LieberburgI.,
PrusinerS. B.,
LingappaV. R.1987; Biogenesis and transmembrane orientation of the cellular isoform of the scrapie prion protein. Molecular and Cellular Biology 7:914–920
HopeJ.,
HunterN.1988; Scrapie-associated fibrils, PrP protein and the Sinc gene. In Novel Infectious Agents and The Central Nervous System Ciba Foundation Symposium vol 135 pp 146–158 Edited by
BockG.,
MarshJ.
London: Wiley-Interscience Publication;
HopeJ.,
ReekieL. D.,
HunterN.,
MulthaupG.,
BeyreutherK.,
WhiteH.,
ScottA. C.,
StackM. J.,
DawsonM.,
WellsG. A. H.1988; Fibrils from brains of cows with new cattle disease contain scrapie-associated protein. Nature, London 336:390–392
HsiaoK.,
BakerH. F.,
CrowT. J.,
PoulterM.,
OwenF.,
TerwilligerJ. D.,
WestawayD.,
OttJ.,
PrusinerS. B.1989; Linkage of a prion protein missense variant to Gerstmann-Straussler syndrome. Nature, London 338:342–345
HunterN.,
HopeJ.,
McConnellI.,
DickinsonA. G.1987; Linkage of the scrapie-associated fibril protein (PrP) gene and Sinc using congenic mice and restriction fragment length polymorphism analysis. Journal of General Virology 68:2711–2716
HunterN.,
FosterJ. D.,
DickinsonA. G.,
HopeJ.1989; Linkage of the gene for the scrapie-associated fibril protein (PrP) to the sip gene in Cheviot sheep. Veterinary Record 124:364–366
HunterN.,
FosterJ. D.,
BensonG.,
HopeJ.1991; Restriction fragment length polymorphisms of the scrapie-associated fibril protein (PrP) gene and their association with susceptibility to natural scrapie in British sheep. Journal of General Virology 72:1287–1292
KretzschmarH. A.,
StowringL. E.,
WestawayD.,
StubblebineW. H.,
PrusinerS. B.,
DeArmondS. J.1986; Molecular cloning of a human prion protein cDNA. DNA 5:315–324
LaplancheJ. L.,
ChatelainJ.,
LaunayJ. M.,
GazengelC.,
VidaudM.1990; Deletion in prion protein gene in a Moroccan family. Nucleic Acids Research 18:6745
LochtC.,
ChesebroB.,
RaceR.,
KeithJ. M.1986; Molecular cloning and complete sequence of prion protein cDNA from mouse brain infected with the scrapie agent. Proceedings of the National Academy of Sciences, U.S.A 83:6372–6376
LowensteinD. H.,
ButlerD. A.,
WestawayD.,
McKinleyM. P.,
DeArmondS. J.,
PrusinerS. B.1990; Three hamster species with different scrapie incubation times and neuropathological features encode distinct prion proteins. Molecular and Cellular Biology 10:1153–1163
MerzP. A.,
SomervilleR. A.,
WisniewskiH. M.,
ManuelidisL.,
ManuelidisE.1983; Scrapie-associated fibrils in Creutzfeldt-Jakob disease. Nature, London 306:474–476
OwenF.,
PoulterM.,
ShahT.,
CollingeJ.,
LofthouseR.,
BakerH.,
RidleyR.,
McVeyJ.,
CrowT.1990; An in-frame insertion in the prion protein gene in familial Creutzfeldt-Jakob disease. Molecular Brain Research 7:273–276
RaceR. E.,
GrahamK.,
ErnstD.,
CaugheyB.,
ChesebroB.1998; Analysis of linkage between scrapie incubation period and the prion protein gene in mice. Journal of General Virology 71:493–497
RogersM.,
TaraboulosA.,
ScottM.,
GrothD.,
PrusinerS. B.1990; Intracellular accumulation of the cellular prion protein after mutagenesis of its Asn-linked glycosylation sites. Glycobiology 1:101–109
SaikiR. K.,
ScharfS. J.,
FaloonaF.,
MullisK. B.,
HornG. T.,
ErlichH. A.,
ArnheimN.1985; Enzymatic amplification of β -globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science 230:1350–1354
TagliaviniF.,
PrelliF.,
GhisoJ.,
BugianiO.,
SerbanD.,
PrusinerS. B.,
FarlowM. R.,
GhettiB.,
FrangioneB.1991; Amyloid protein of Gerstmann-Sträussler-Scheinker disease (Indiana kindred) is an 11 kd fragment of prion protein with an N-terminal glycine at codon 58. EMBO Journal 10:513–519
WestawayD.,
GoodmanP. A.,
MirendaC. A.,
McKinleyM. P.,
CarlsonG. A.,
PrusinerS. B.1987; Distinct prion proteins in short and long scrapie incubation period mice. Cell 51:651–662
WestawayD.,
MirendaC. A.,
FosterD.,
ZebarjadianY.,
ScottM.,
TorchiaM.,
YangS.-L.,
SerbanH.,
DeArmondS. J.,
EbelingC.,
PrusinerS. B.,
CarlsonG. A.1991; Paradoxical shortening of scrapie incubation times by expression of prion protein transgenes derived from long incubation period mice. Neuron (in press)
YostC. S.,
LopezC. D.,
PrusinerS. B.,
MyersR. M.,
LingappaV. R.1990; Non-hydrophobic extracytoplasmic determinant of stop transfer in the prion protein. Nature, London 343:669–672