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. 1994 Jul 5;91(14):6418–6422. doi: 10.1073/pnas.91.14.6418

Structure and polymorphism of the mouse prion protein gene.

D Westaway 1, C Cooper 1, S Turner 1, M Da Costa 1, G A Carlson 1, S B Prusiner 1
PMCID: PMC44213  PMID: 7912827

Abstract

Missense mutations in the prion protein (PrP) gene, overexpression of the cellular isoform of PrP (PrPC), and infection with prions containing the scrapie isoform of PrP (PrPSc) all cause neurodegenerative disease. To understand better the physiology and expression of PrPC, we retrieved mouse PrP gene (Prn-p) yeast artificial chromosome (YAC), cosmid, phage, and cDNA clones. Physical mapping positions Prn-p approximately 300 kb from ecotropic virus integration site number 4 (Evi-4), compatible with failure to detect recombination between Prn-p and Evi-4 in genetic crosses. The Prn-pa allele encompasses three exons, with exons 1 and 2 encoding the mRNA 5' untranslated region. Exon 2 has no equivalent in the Syrian hamster and human PrP genes. The Prn-pb gene shares this intron/exon structure but harbors an approximately 6-kb deletion within intron 2. While the Prn-pb open reading frame encodes two amino acid substitutions linked to prolonged scrapie incubation periods, a deletion of intron 2 sequences also characterizes inbred strains such as RIII/S and MOLF/Ei with shorter incubation periods, making a relationship between intron 2 size and scrapie pathogenesis unlikely. The promoter regions of a and b Prn-p alleles include consensus Sp1 and AP-1 sites, as well as other conserved motifs which may represent binding sites for as yet unidentified transcription factors.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Angel P., Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1991 Dec 10;1072(2-3):129–157. doi: 10.1016/0304-419x(91)90011-9. [DOI] [PubMed] [Google Scholar]
  2. Baldwin T. J., Burden S. J. Muscle-specific gene expression controlled by a regulatory element lacking a MyoD1-binding site. Nature. 1989 Oct 26;341(6244):716–720. doi: 10.1038/341716a0. [DOI] [PubMed] [Google Scholar]
  3. Basler K., Oesch B., Scott M., Westaway D., Wälchli M., Groth D. F., McKinley M. P., Prusiner S. B., Weissmann C. Scrapie and cellular PrP isoforms are encoded by the same chromosomal gene. Cell. 1986 Aug 1;46(3):417–428. doi: 10.1016/0092-8674(86)90662-8. [DOI] [PubMed] [Google Scholar]
  4. Burke D. T., Rossi J. M., Leung J., Koos D. S., Tilghman S. M. A mouse genomic library of yeast artificial chromosome clones. Mamm Genome. 1991;1(1):65–65. doi: 10.1007/BF00350849. [DOI] [PubMed] [Google Scholar]
  5. Büeler H., Aguzzi A., Sailer A., Greiner R. A., Autenried P., Aguet M., Weissmann C. Mice devoid of PrP are resistant to scrapie. Cell. 1993 Jul 2;73(7):1339–1347. doi: 10.1016/0092-8674(93)90360-3. [DOI] [PubMed] [Google Scholar]
  6. Carlson G. A., Ebeling C., Torchia M., Westaway D., Prusiner S. B. Delimiting the location of the scrapie prion incubation time gene on chromosome 2 of the mouse. Genetics. 1993 Apr;133(4):979–988. doi: 10.1093/genetics/133.4.979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carlson G. A., Ebeling C., Yang S. L., Telling G., Torchia M., Groth D., Westaway D., DeArmond S. J., Prusiner S. B. Prion isolate specified allotypic interactions between the cellular and scrapie prion proteins in congenic and transgenic mice. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5690–5694. doi: 10.1073/pnas.91.12.5690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carlson G. A., Goodman P. A., Lovett M., Taylor B. A., Marshall S. T., Peterson-Torchia M., Westaway D., Prusiner S. B. Genetics and polymorphism of the mouse prion gene complex: control of scrapie incubation time. Mol Cell Biol. 1988 Dec;8(12):5528–5540. doi: 10.1128/mcb.8.12.5528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Carlson G. A., Kingsbury D. T., Goodman P. A., Coleman S., Marshall S. T., DeArmond S., Westaway D., Prusiner S. B. Linkage of prion protein and scrapie incubation time genes. Cell. 1986 Aug 15;46(4):503–511. doi: 10.1016/0092-8674(86)90875-5. [DOI] [PubMed] [Google Scholar]
  10. Chen E. Y., Seeburg P. H. Supercoil sequencing: a fast and simple method for sequencing plasmid DNA. DNA. 1985 Apr;4(2):165–170. doi: 10.1089/dna.1985.4.165. [DOI] [PubMed] [Google Scholar]
  11. Chesebro B., Race R., Wehrly K., Nishio J., Bloom M., Lechner D., Bergstrom S., Robbins K., Mayer L., Keith J. M. Identification of scrapie prion protein-specific mRNA in scrapie-infected and uninfected brain. Nature. 1985 May 23;315(6017):331–333. doi: 10.1038/315331a0. [DOI] [PubMed] [Google Scholar]
  12. Devary Y., Gottlieb R. A., Lau L. F., Karin M. Rapid and preferential activation of the c-jun gene during the mammalian UV response. Mol Cell Biol. 1991 May;11(5):2804–2811. doi: 10.1128/mcb.11.5.2804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Devary Y., Gottlieb R. A., Smeal T., Karin M. The mammalian ultraviolet response is triggered by activation of Src tyrosine kinases. Cell. 1992 Dec 24;71(7):1081–1091. doi: 10.1016/s0092-8674(05)80058-3. [DOI] [PubMed] [Google Scholar]
  14. Dickinson A. G., Meikle V. M., Fraser H. Identification of a gene which controls the incubation period of some strains of scrapie agent in mice. J Comp Pathol. 1968 Jul;78(3):293–299. doi: 10.1016/0021-9975(68)90005-4. [DOI] [PubMed] [Google Scholar]
  15. Gabizon R., McKinley M. P., Groth D., Prusiner S. B. Immunoaffinity purification and neutralization of scrapie prion infectivity. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6617–6621. doi: 10.1073/pnas.85.18.6617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Goldgaber D. Anticipating the anti-prion protein? Nature. 1991 May 9;351(6322):106–106. doi: 10.1038/351106a0. [DOI] [PubMed] [Google Scholar]
  17. Green E. D., Olson M. V. Systematic screening of yeast artificial-chromosome libraries by use of the polymerase chain reaction. Proc Natl Acad Sci U S A. 1990 Feb;87(3):1213–1217. doi: 10.1073/pnas.87.3.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hattori M., Sakaki Y. Dideoxy sequencing method using denatured plasmid templates. Anal Biochem. 1986 Feb 1;152(2):232–238. doi: 10.1016/0003-2697(86)90403-3. [DOI] [PubMed] [Google Scholar]
  19. Hidaka K., Yamamoto I., Arai Y., Mukai T. The MEF-3 motif is required for MEF-2-mediated skeletal muscle-specific induction of the rat aldolase A gene. Mol Cell Biol. 1993 Oct;13(10):6469–6478. doi: 10.1128/mcb.13.10.6469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hsiao K., Baker H. F., Crow T. J., Poulter M., Owen F., Terwilliger J. D., Westaway D., Ott J., Prusiner S. B. Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome. Nature. 1989 Mar 23;338(6213):342–345. doi: 10.1038/338342a0. [DOI] [PubMed] [Google Scholar]
  21. Hunter N., Hope J., McConnell I., Dickinson A. G. Linkage of the scrapie-associated fibril protein (PrP) gene and Sinc using congenic mice and restriction fragment length polymorphism analysis. J Gen Virol. 1987 Oct;68(Pt 10):2711–2716. doi: 10.1099/0022-1317-68-10-2711. [DOI] [PubMed] [Google Scholar]
  22. Iwasaki M., Okumura K., Kondo Y., Tanaka T., Igarashi H. cDNA cloning of a novel heterogeneous nuclear ribonucleoprotein gene homologue in Caenorhabditis elegans using hamster prion protein cDNA as a hybridization probe. Nucleic Acids Res. 1992 Aug 11;20(15):4001–4007. doi: 10.1093/nar/20.15.4001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Larsen F., Gundersen G., Prydz H. Choice of enzymes for mapping based on CpG islands in the human genome. Genet Anal Tech Appl. 1992 Jun;9(3):80–85. doi: 10.1016/1050-3862(92)90002-m. [DOI] [PubMed] [Google Scholar]
  24. Lee W., Mitchell P., Tjian R. Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. Cell. 1987 Jun 19;49(6):741–752. doi: 10.1016/0092-8674(87)90612-x. [DOI] [PubMed] [Google Scholar]
  25. Lindsay S., Bird A. P. Use of restriction enzymes to detect potential gene sequences in mammalian DNA. 1987 May 28-Jun 3Nature. 327(6120):336–338. doi: 10.1038/327336a0. [DOI] [PubMed] [Google Scholar]
  26. Locht C., Chesebro B., Race R., Keith J. M. Molecular cloning and complete sequence of prion protein cDNA from mouse brain infected with the scrapie agent. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6372–6376. doi: 10.1073/pnas.83.17.6372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Loh E. Y., Elliott J. F., Cwirla S., Lanier L. L., Davis M. M. Polymerase chain reaction with single-sided specificity: analysis of T cell receptor delta chain. Science. 1989 Jan 13;243(4888):217–220. doi: 10.1126/science.2463672. [DOI] [PubMed] [Google Scholar]
  28. Manson J., West J. D., Thomson V., McBride P., Kaufman M. H., Hope J. The prion protein gene: a role in mouse embryogenesis? Development. 1992 May;115(1):117–122. doi: 10.1242/dev.115.1.117. [DOI] [PubMed] [Google Scholar]
  29. McKinley M. P., Bolton D. C., Prusiner S. B. A protease-resistant protein is a structural component of the scrapie prion. Cell. 1983 Nov;35(1):57–62. doi: 10.1016/0092-8674(83)90207-6. [DOI] [PubMed] [Google Scholar]
  30. Moser M., Oesch B., Büeler H. An anti-prion protein? Nature. 1993 Mar 18;362(6417):213–214. doi: 10.1038/362213b0. [DOI] [PubMed] [Google Scholar]
  31. Oesch B., Westaway D., Wälchli M., McKinley M. P., Kent S. B., Aebersold R., Barry R. A., Tempst P., Teplow D. B., Hood L. E. A cellular gene encodes scrapie PrP 27-30 protein. Cell. 1985 Apr;40(4):735–746. doi: 10.1016/0092-8674(85)90333-2. [DOI] [PubMed] [Google Scholar]
  32. Prusiner S. B., Groth D., Serban A., Stahl N., Gabizon R. Attempts to restore scrapie prion infectivity after exposure to protein denaturants. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2793–2797. doi: 10.1073/pnas.90.7.2793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Prusiner S. B. Molecular biology of prion diseases. Science. 1991 Jun 14;252(5012):1515–1522. doi: 10.1126/science.1675487. [DOI] [PubMed] [Google Scholar]
  34. Puckett C., Concannon P., Casey C., Hood L. Genomic structure of the human prion protein gene. Am J Hum Genet. 1991 Aug;49(2):320–329. [PMC free article] [PubMed] [Google Scholar]
  35. Robakis N. K., Sawh P. R., Wolfe G. C., Rubenstein R., Carp R. I., Innis M. A. Isolation of a cDNA clone encoding the leader peptide of prion protein and expression of the homologous gene in various tissues. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6377–6381. doi: 10.1073/pnas.83.17.6377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Schwartz D. C., Cantor C. R. Separation of yeast chromosome-sized DNAs by pulsed field gradient gel electrophoresis. Cell. 1984 May;37(1):67–75. doi: 10.1016/0092-8674(84)90301-5. [DOI] [PubMed] [Google Scholar]
  37. Shapiro M. B., Senapathy P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 1987 Sep 11;15(17):7155–7174. doi: 10.1093/nar/15.17.7155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Westaway D., DeArmond S. J., Cayetano-Canlas J., Groth D., Foster D., Yang S. L., Torchia M., Carlson G. A., Prusiner S. B. Degeneration of skeletal muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins. Cell. 1994 Jan 14;76(1):117–129. doi: 10.1016/0092-8674(94)90177-5. [DOI] [PubMed] [Google Scholar]
  39. Westaway D., Goodman P. A., Mirenda C. A., McKinley M. P., Carlson G. A., Prusiner S. B. Distinct prion proteins in short and long scrapie incubation period mice. Cell. 1987 Nov 20;51(4):651–662. doi: 10.1016/0092-8674(87)90134-6. [DOI] [PubMed] [Google Scholar]
  40. Westaway D., Mirenda C. A., Foster D., Zebarjadian Y., Scott M., Torchia M., Yang S. L., Serban H., DeArmond S. J., Ebeling C. Paradoxical shortening of scrapie incubation times by expression of prion protein transgenes derived from long incubation period mice. Neuron. 1991 Jul;7(1):59–68. doi: 10.1016/0896-6273(91)90074-a. [DOI] [PubMed] [Google Scholar]
  41. Westaway D., Zuliani V., Cooper C. M., Da Costa M., Neuman S., Jenny A. L., Detwiler L., Prusiner S. B. Homozygosity for prion protein alleles encoding glutamine-171 renders sheep susceptible to natural scrapie. Genes Dev. 1994 Apr 15;8(8):959–969. doi: 10.1101/gad.8.8.959. [DOI] [PubMed] [Google Scholar]
  42. Zuberi A. R., Roopenian D. C. High-resolution mapping of a minor histocompatibility antigen gene on mouse chromosome 2. Mamm Genome. 1993 Sep;4(9):516–522. doi: 10.1007/BF00364787. [DOI] [PubMed] [Google Scholar]

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