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Volume 76, Issue 3

Identification of five allelic variants of the sheep PrP gene and their association with natural scrapie Free

Abstract

Scrapie is a fatal neurodegenerative disease of sheep that belongs to the group of prion diseases found in humans and animals. The host encoded prion protein (PrP) plays a central role in the disease process. In the PrP genes of man, mice and sheep, polymorphisms have been found that are associated with disease susceptibility and pathogenesis. We have used denaturing gradient gel electrophoresis (DGGE) to detect polymorphisms in the sheep PrP gene. In addition to the already described polymorphisms at codons 136, 154 and 171, we identified a hitherto unknown G → T transition at codon 171. This transition is responsible for a glutamine to histidine substitution. An arginine to glutamine substitution at this position has been described previously. DGGE allowed us to identify five different combinations of these polymorphisms within the PrP gene representing five allelic variants, which were cloned and sequenced. Based on the triplet sequences present at codons 136, 154 and 171 these allelic variants were designated PrP, PrP, PrP, PrP and PrP. To determine the association of these allelic variants with natural scrapie, we screened 34 scrapie affected and 91 healthy control sheep of the Texel breed for the presence of these allelic variants. In these two groups, the five variants gave rise to 13 different genotypes. The distribution of the allelic variants among both groups showed marked differences. The PrP variant was present with high frequency in scrapie affected sheep, whereas the PrP variant was almost exclusively present in the healthy group. Two other variants, PrP and PrP, were found in both groups with equal frequencies. The data obtained suggest modulation of disease susceptibility in these Texel sheep by at least five different PrP allelic variants, with the PrP and PrP alleles acting in a dominant, but opposite fashion over the PrP and PrP alleles. The frequency of the PrP variant was too low to draw any conclusions.

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© Journal of General Virology 1995
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1995-03-01
2024-04-25
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References

  1. Brotherston J. G., Renwick C. C., Stamp J. T., Zlotnick I. 1968; Spread of scrapie by contact to goats and sheep. Journal of Comparative Pathology 78:9–17
     [Google Scholar]
  2. Carlson G. A., Kingsbury D. T., Goodman P. A., Coleman S., Marshall S. T., Dearmond S., Westaway D., Prusiner S. B. 1986; Linkage of prion protein and scrapie incubation time genes. Cell 46:503–511
     [Google Scholar]
  3. Collinge J., Palmer M. S., Dryden A. J. 1991; Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease. Lancet 337:1441–1442
     [Google Scholar]
  4. Dickinson A. G., Young G. B., Stamp J. T., Renwick C. C. 1965; An analysis of natural scrapie in Suffolk sheep. Heredity 20:485–503
     [Google Scholar]
  5. Dickinson A. G., Stamp J. T., Renwick C. C. 1974; Maternal and lateral transmission of scrapie in sheep. Journal of Comparative Pathology 84:19–25
     [Google Scholar]
  6. Dickinson A. G., Outram G. W. 1988; Genetic aspects of unconventional virus infections: the basis of the virino hypothesis. In Novel Infectious Agents of the Central Nervous System Ciba Foundation Symposium vol 13563–83 Edited by Bock G., Marsh J. London: Wiley-Interscience;
     [Google Scholar]
  7. Goldfarb L. G., Petersen R. B., Tabaton M., Brown P., Leblanc A. C., Montagna P., Cortelli P., Julien J., Vital C., Pendelbury W. W., Haltia M., Wills P. R., Hauw J. J., McKeever P. E., Monari L., Schrank B., Swergold G. D., Autilio-Gambetti L., Gajdusek D. C., Lugaresi E., Gambetti P. 1992; Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science 258:806–808
     [Google Scholar]
  8. Goldmann W., Hunter N., Foster J. D., Salbaum J. M., Beyreuther K., Hope J. 1990; Two alleles of a neural protein gene linked to scrapie in sheep. Proceedings of the National Academy of Sciences, USA 87:2476–2480
     [Google Scholar]
  9. Goldmann W., Hunter N., Benson G., Foster J. D., Hope J. 1991a; Different scrapie-associated fibril proteins (PrP) are encoded by lines of sheep selected for different alleles of the Sip gene. Journal of General Virology 72:2411–2417
     [Google Scholar]
  10. Goldmann W., Hunter N., Martin T., Dawson M., Hope J. 1991b; 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
     [Google Scholar]
  11. Goldmann W., Hunter N., Smith G., Foster J., Hope J. 1994; PrP genotype and agent effects in scrapie: change in allelic interaction with different isolates of agent in sheep, a natural host of scrapie. Journal of General Virology 75:989–995
     [Google Scholar]
  12. Hsiao K., Scott M., Foster D., Groth D., Dearmond S., Prusiner S. 1990; Spontaneous neurodegeneration in transgenic mice with mutant prion protein of Gerstmann-Straussler syndrome. Science 250:1587–1590
     [Google Scholar]
  13. Hunter N., Hope J., McConnell I., Dickinson A. G. 1987; Linkage of the scrapie-associated fibril protein (PrP) gene and Sine using congenic mice and restriction fragment length polymorphism analysis. Journal of General Virology 68:2711–2716
     [Google Scholar]
  14. Hunter N., Foster J. D., Dickinson A. G., Hope J. 1989; Linkage of the gene for the scrapie-associated fibril protein (PrP) to the Sip gene in Cheviot sheep. Veterinary Record 124:364–366
     [Google Scholar]
  15. Hunter N., Foster J. D., Benson G., Hope J. 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
     [Google Scholar]
  16. Hunter N., Goldmann W., Benson G., Foster J. D., Hope J. 1993; Swaledale sheep affected by natural scrapie differ significantly in PrP genotype frequencies from healthy sheep and those selected for reduced incidence of scrapie. Journal of General Virology 74:1025–1031
     [Google Scholar]
  17. Laplanche J. L., Chatelain J., Westaway D., Thomas S., Dussaucy M., Brugere-Picoux J., Launay J. M. 1993; PrP polymorphisms associated with natural scrapie discovered by denaturing gradient gel electrophoresis. Genomics 15:30–37
     [Google Scholar]
  18. Lerman L. S., Silverstein K. 1987; Computational simulation of DNA melting and its application to denaturing gradient gel electrophoresis. Methods in Enzymology 155:482–501
     [Google Scholar]
  19. Lichtenauer-Kaligis E. G. R., Thussen J., den Dulk H., Van de Putte P., Tasseron-de Jong J. G., Giphart-Gassler M. 1993; Genome wide spontaneous mutation in human cells determined by the spectrum of mutations in hprt cDNA genes. Mutagenesis 8:207–220
     [Google Scholar]
  20. Maciulis A., Hunter N., Wang S., Goldmann W., Hope J., Foote W. 1992; Polymorphisms of a scrapie-associated fibril protein (PrP) gene and their association with susceptibility to experimentally induced scrapie in Cheviot sheep in the United States. American Journal of Veterinary Research 53:1957–1960
     [Google Scholar]
  21. Myers R. M., Maniatis T., Lerman L. S. 1987; Detection and localization of single bases changes by denaturing gradient gel electrophoresis. Methods in Enzymology 155:501–527
     [Google Scholar]
  22. Owen F., Poulter M., Lofthouse R., Collinge J., Crow T. J., Risby D., Baker H. F., Ridley R. M., Hsiao K., Prusiner S. B. 1989; Insertion in prion protein gene in familial Creutzfeldt-Jakob disease. Lancet i:51–52
     [Google Scholar]
  23. Owen F., Poulter M., Collinge J., Leach M., Shah T., Lofthouse R., Chen Y. F., Crow T. J., Harding A. E., Hardy J., Rossor M. N. 1991; Insertions in the prion protein gene in atypical dementias. Experimental Neurology 112:240–242
     [Google Scholar]
  24. Palmer M. S., Dryden A. J., Hughes J. T., Collinge J. 1991; Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 352:340–342
     [Google Scholar]
  25. Parry H. B. 1962; Scrapie: a transmissible and hereditary disease of sheep. Heredity 17:75–105
     [Google Scholar]
  26. Prusiner S. B. 1991; Molecular biology of prion diseases. Science 252:1515–1522
     [Google Scholar]
  27. Prusiner S. B. 1993; Genetic and infectious prion diseases. Archives in Neurology 50:1129–1153
     [Google Scholar]
  28. Sambrook J., Fritsch E. F., Maniatis T. 1989 Molecular Cloning: A Laboratory Manual 2nd edn New York: Cold Spring Harbor Laboratory;
     [Google Scholar]
  29. Sanger F., Niklen S., Coulson A. R. 1977; DNA sequencing with chain-terminating inhibitors. Proceedings of the National Acadademy of Sciences, USA 74:5463–5467
     [Google Scholar]
  30. Schreuder B. E. C., De Jong M. C. M., Pekelder J. J., Vellema P., Broker A. J. M., Betcke H. 1993; Prevalence and incidence of scrapie in the Netherlands: a questionnaire survey. Veterinary Record 133:211–214
     [Google Scholar]
  31. Stahl N., Prusiner S. B. 1991; Prions and prion proteins. FASEB Journal 5:2799–2807
     [Google Scholar]
  32. van Keulen L. J. M., Schreuder B. E. C., Meloen R. H., Poelen-van der berg M., Mood-Harkes G., Vromans M. E. W., Langeveld L. 1995; Immunohistochemical detection and localization of prion protein in brain tissue of sheep with natural scrapie. Veterinary Pathology (in press)
    [Google Scholar]
  33. Westaway D., Zuliani V., Cooper C. M., Dacosta M., Neuman S., Jenny A. L., Detwiler L., Prusiner S. B. 1994; Homozygosity for prion protein alleles encoding glutamine-171 renders sheep susceptible to natural scrapie. Genes and Development 8959–969
     [Google Scholar]
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Identification of five allelic variants of the sheep PrP gene and their association with natural scrapie
J. Gen. Virol. 76, 509 (1995); https://doi.org/10.1099/0022-1317-76-3-509
/content/journal/jgv/10.1099/0022-1317-76-3-509
/content/journal/jgv/10.1099/0022-1317-76-3-509
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