Summary
The prion protein (PrP), first identified in scrapie-infected rodents, is encoded by a single-copy chromosomal gene. PrP genes are conserved and have been identified in 13 species of mammals. Cloning and analysis of the PrP gene has revealed that pathogenic (PrPSc) and cellular (PrPC) isoforms of the prion protein do not reflect alternative splicing events but instead share the same amino acid sequence: these data first suggested the hypothesis that prion isoforms are alternate conformers1. However, at this time the mechanism involved in the transition between PrPC and PrPSc is obscure, as is the normal function of PrPC. We have therefore sought to identify PrP-linked genes that might feature in conformational transitions, and conserved regulatory elements that might offer insights into the physiology of PrPC. Accordingly, 145 kb of DNA from human and sheep PrP genes, and two alleles of Prn-p has been analysed for conserved regions, ORFs, potential exons, repetitive sequences, putative CpG islands, and possible polymorphic motifs. These sequences reveal unexpected features within the wild-type PrP genes of each of these species. The predominant allele of the mouse gene, Prn-pa, found in 44 inbred laboratory strains contains a 6878 nucleotide retroviral genome inserted into the anticoding strand of intron 2. This intracisternal A particle (IAP) element is (i) flanked by duplications of a AAGCTT nucleotide motif found once in the Prn-pb gene, and (ii) highly related to a transpositionally-competent prototype IAP element, differing principally in small deletion of the pol gene: these data are indicative of a recent transpositional orgin. In the case of the sheep PrP gene, the unusually long 3′ untranslated region (UTR) reflects in most part the presence of a “fossil” 1.2 kb mariner-like transposable element, which is absent from the human and mouse PrP genes. Chromosomal instability associated with mariner-like elements on chromosome 17 in humans suggests that DNA rearrangements may take place adjacent to the PrP gene in sheep, and also in cattle (which also exhibit an extended 3′ UTR and presumably harbor a mariner-like element). Lastly, the large intron of the human PrP gene contains a sequence analogous to exon 2 of the mouse and sheep PrP genes, flanked by consensus splice acceptor and donor sites: while it remains to be established that “exon 2” sequences are included in a subset of human PrP mRNAs, these data indicate that an ancestral PrP gene most likely exhibited a three exon structure.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Akowitz, A., E. E. Manuelidis and L. Manuelidis. (1993). Protected endogenous retroviral sequences copurify with infectivity in experimental Creutzfeldt-Jakob disease. Arch. Virol. 130: 301–316.
Akowitz, A., T. Sklaviadis and L. Manuelidis. (1994). Endogenous viral complexes with long RNA cosediment with the agent of Creutzfeldt-Jakob disease. Nucleic Acids Res. 22: 1101–1107.
Amouyel, P., Vidal, O., Launay, J.-M., and Laplanche J.-L. (1995). The apoliloprotein E alleles as major susceptibility factors for Creutzfeldt-Jakob Disease. Lancet 344: 1315–1318.
Auge-Gouillou, C., Y. Bigot, N. Pollet, M. H. Hamelin, M. Meunier-Rotival and G. Periquet. (1995). Human and other mammalian genomes contain transposons of the mariner family. FEBS letters 368: 541–546.
Baldwin, M. A., F. E. Cohen and S. B. Prusiner. (1995). Prion protein isoforms, a convergence of biological and structural investigations. J. Biol. Chem. 270: 19197–19200.
Bessen, R. A., Kocisko, D.A., Raymond, G.J., Nandan, S., Lansbury, P.T., and Caughey, B. (1995). Non-genetic propagation of strain-specific properties of scrapie prion protein. Nature 375: 698–700.
Bessen, R. A. and R. F. Marsh. (1992). Identification of two biologically distinct strains of transmissible mink encephalopathy in hamsters. J. Gen. Virol. 73: 329–334.
Bruce, M. E. (1993). Scrapie strain variation and mutation. Brit. Med. Bul 49(4): 822–838.
Bueler, H., M. Fischer, Y. Lang, H. Bluethmann, H.-P. Lipp, S. J. DeArmand, S. B. Prusiner, M. Aguet and C. Weissmann. (1992). Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356: 577–582.
Carlson, G. A., C. Ebeling, S.-L. Yang, G. Telling, M. Torchia, D. Groth, D. Westaway, S. J. DeArmond and S. B. Prusiner. (1994). Prion isolate specified allotypic interactions between the cellular and scrapie prion proteins in congenic and transgenic mice. Proc. Natl. Acad. Sci. USA 91: 5690–5694.
Carlson, G. A., P. A. Goodman, M. Lovett, B. A. Taylor, S. T. Marshall, M. Peterson-Torchia, D. Westaway and S. B. Prusiner. (1988). Genetics and polymorphism of the mouse prion gene complex: the control of scrapie incubation time. Mol. Cell. Biol. 8: 5528–5540.
Carlson, G. A., D. T. Kingsbury, P. A. Goodman, S. Coleman, S. T. Marshall, S. J. DeArmond, D. Westaway and S. B. Prusiner. (1986). Linkage of prion protein and scrapie incubation time genes. Cell 46: 503–511.
Cohen, F. E., K.-M. Pan, Z. Huang, M. Baldwin, R. J. Fletterick and S. B. Prusiner. (1994). Structural clues to prion replication. Science 264: 530–531.
Doh-ura, K., S. Perryman, R. Race and B. Chesebro. (1995). Identification of differentially expressed genes in scrapie-infected mouse neuroblastoma cells. Microbial Pathogenesis 18: 1–9.
Gabriel, J.-M., B. Oesch, H. Kretzschmar, M. Scott and S. B. Prusiner. (1992). Molecular cloning of a candidate chicken prion protein. Proc. Natl. Acad. Sci. USA 89: 9097–9101.
Gabriel, J.-M., B. Oesch, M. Scott and S. B. Prusiner (1991). Molecular cloning and evolutionary analysis of a candidate chicken prion protein. Priori Diseases in Humans and Animals Symposium, London, Sept. 2–4, 1991.
Goldfarb, L. G., P. Brown, W. R. McCombie, D. Goldgaber, G. D. Swergold, P. R. Wills, L. Cervenakova, H. Baron, C. J. J. Gibbs and D. C. Gajdusek. (1991). Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene. Proc. Natl. Acad Sci. USA 88: 10926–10930.
Goldmann, W., N. Hunter, J. D. Foster, J. M. Salbaum, K. Beyreuther and J. Hope. (1990). Two alleles of a neural protein gene linked to scrapie in sheep. Proc. Natl. Acad Sci. USA 87: 2476–2480.
Hsiao, K., H. F. Baker and T. J. Crow. (1989). Linkage of a prion protein missense variant to Gerstmann-Straussler Syndrome. Nature 338: 342–345.
Hsiao, K. K., D. Groth, M. Scott, S.-L. Yang, A. Serban, D. Rapp, D. Foster, M. Torchia, S. J. DeArmond and S. B. Prusiner (1992). Genetic and transgenic studies of prion proteins in Gerstmann-Straussler-Scheinker disease. Prion Diseases of Humans and Animals. S. B. Prusiner, J. Collinge, J. Powell and B. Anderton. London, Ellis Horwood: 120–128.
Kretzschmar, H. A., L. E. Stowring, D. Westaway, W. H. Stubblebine, S. B. Prusiner and S. J. DeArmond. (1986). Molecular cloning of a human prion protein cDNA. DNA 5: 315–324.
Kuff, E. L. and K. K. Lueders (1988). The intracisternal A-Particle gene family: structure and functional aspects. Advances in Cancer Research 51(183–276).
Li, G. and D. C. Bolton (1996). A novel prion protein mRNA contains an extra exon:increased expression in scrapie. Brain Research. in press.
Manson, J. C., A. R. Clarke, M. L. Hooper, L. Aitchison, I. McConnel and J. Hope. (1994). 129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal. Molecular Neurobiology 8: 121–127.
Medori, R., H.-J. Tritschler, A. LeBlanc, F. Villare, V. Manetto, H. Y. Chen, R. Xue, S. Leal, P. Montagna, P. Cortelli, P. Tinuper, P. Avoni, M. Mochi, A. Baruzzi, J. J. Hauw, J. Ott, E. Lugaresi, L. Autilio-Gambetti and P. Gambetti. (1992). Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. N. Engl. J. Med. 326: 444–449.
Oesch, B., D. Westaway and S. B. Prusiner. (1991). Prion protein genes: evolutionary and functional aspects. Curr. Top. Microbiol. Immunol. 172: 109–124.
Oosumi, T., W. R. Belknap and B. Garlick (1995). Mariner transposons in humans. Nature 378: 672.
Prusiner, S. B., M. Scott, D. Foster, K.-M. Pan, D. Groth, C. Mirenda, M. Torchia, S.-L. Yang, D. Serban, G. A. Carlson, P. C. Hoppe, D. Westaway and S. J. DeArmond. (1990). Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 63: 673–686.
Puckett, C., P. Concannon, C. Casey and L. Hood. (1991). Genomic structure of the human prion protein gene. Am. J. Hum. Genet. 49: 320–329.
Rieter, L. T., T. Murakami, T. Koeuth, L. Pentao, D. M. Muzny, R. A. Gibbs and J. R. Lupski. (1996). A recombination hotspot responsible for two inherited peripheral neuropathies is located near a mariner transposon-like element. Nature genetics 12: 288–297.
Robertson, H. M. (1995). J. Insect Physiology 41: 99–105.
Sakaguchi, S., S. Katamine, N. Nishida, R. Moriuchi, K. Shigematsu, T. Sugimoto, A. Nakatani, Y. Kataoka, T. Houtani, S. Shirabe, H. Okada, S. Hasegawa, T. Miyamoto and T. Noda. (1996). Loss of cerebellar purkinje cells in aged mice homozygous for a disrupted PrP gene. Nature 380: 528–531.
Saunders, A. M., K. Schmader, J. C. S. Breitner and e. al. (1993). Apolipoprotein E epsilon 4 allele distributions in late-onset Alzheimer’s Disease and in other amyloid-forming diseases. Lancet 342: 710–711.
Schätzl, H. M., M. Da Costa, L. Taylor, F. E. Cohen and S. B. Prusiner. (1994). Prion protein gene variation among primates. J. Mol. Biol. 245: 362–374.
Sparkes, R. S., M. Simon, V. H. Cohn, R. E. K. Fournier, J. Lern, I. Klisak, C. Heinzmann, C. Blatt, M. Lucero, T. Mohandas, S. J. DeArmond, D. Westaway, S. B. Prusiner and L. P. Weiner. (1986). Assignment of the human and mouse prion protein genes to homologous chromosomes. Proc. Natl. Acad. Sci. USA 83: 7358–7362.
Stahl, N., D. R. Borchelt, K. Hsiao and S. B. Prusiner. (1987). Scrapie prion protein contains a phosphatidylinositol glycolipid. Cell 51: 229–240.
Telling, G. C, M. Scott, J. Mastrianni, R. Gabizon, M. Torchia, F. E. Cohen, S. J. DeArmond and S. B. Prusiner. (1995). Prion Propagation in Mice Expressing Human and Chimeric PrP transgenes implicates the Interaction of Cellular PrP with Another Protein. Cell 83: 79–90.
Uberbacher, E. C. and R. J. Mural. (1991). Locating protein-coding regions in human DNA sequences by a multiple sensor-neural network approach. Proc. Natl. Acad. Sci. U.S.A. 88: 11261–11265.
Westaway, D., C. Cooper, S. Turner, M. Da Costa, G. A. Carlson and S. B. Prusiner. (1994). Structure and polymorphism of the mouse prion protein gene. Proc. Natl. Acad. Sci. USA 91: 6418–6422.
Westaway, D., S. J. DeArmond, J. Cayetano-Canlas, D. Groth, D. Foster, S.-L. Yang, M. Torchia, G. A. Carlson and S. B. Prusiner. (1994). Degeneration of skeletal N. muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins. Cell 76: 117–129.
Westaway, D., P. A. Goodman, C. A. Mirenda, M. P. McKinley, G. A. Carlson and S. B. Prusiner. (1987). Distinct prion proteins in short and long scrapie incubation period mice. Cell 51: 651–662.
Westaway, D., V. Zuliani, C. M. Cooper, M. Da Costa, S. Neuman, A. L. Jenny, L. Detwiler and S. B. Prusiner. (1994). Homozygosity for prion protein alleles-encoding glutamine-171 renders sheep susceptible to natural scrapie. Genes Dev. 8: 959–969.
Windl, O., M. Dempster, P. Estibeiro and R. Lathe. (1995). A candidate marsupial PrP gene reveals two domains conserved in mammalian PrP proteins. Gene 159: 181–186.
Yoshimoto, J., T. Iinuma, N. Ishiguro, M. Horiuchi, M. Imamura and M. Shinagawa. (1992). Comparative sequence analysis and expression of bovine PrP gene in mouse L-929 cells. Virus Genes 6: 343–356.
Zerr, I., M. Helmhold and T. Weber. (1994). Apolipoprotein E in Creutzfeldt-Jakob Disease [letter]. Lancet 345: 68–69.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1998 Springer Science+Business Media New York
About this chapter
Cite this chapter
Lee, I. et al. (1998). Large-Scale Sequencing of Human, Mouse, and Sheep Prion Protein Genes. In: Morrison, D.R.O. (eds) Prions and Brain Diseases in Animals and Humans. NATO ASI Series, vol 295. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-1896-3_8
Download citation
DOI: https://doi.org/10.1007/978-1-4899-1896-3_8
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4899-1898-7
Online ISBN: 978-1-4899-1896-3
eBook Packages: Springer Book Archive