Acta Neuropathologica

, Volume 121, Issue 1, pp 21–37 | Cite as

Genetic Creutzfeldt–Jakob disease and fatal familial insomnia: insights into phenotypic variability and disease pathogenesis

  • Sabina Capellari
  • Rosaria Strammiello
  • Daniela Saverioni
  • Hans Kretzschmar
  • Piero ParchiEmail author


Human prion diseases are a group of rare neurodegenerative disorders characterized by the conversion of the constitutively expressed prion protein, PrPC, into an abnormally aggregated isoform, called PrPSc. While most people who develop a prion disease have no identifiable cause and a few acquire the disease through an identified source of infection, about 10–15% of patients are affected by a genetic form and carry either a point mutation or an insertion of octapeptide repeats in the prion protein gene. Prion diseases show the highest extent of phenotypic heterogeneity among neurodegenerative disorders and comprise three major disease entities with variable though overlapping phenotypic features: Creutzfeldt–Jakob disease (CJD), fatal insomnia and the Gerstmann–Sträussler–Scheinker syndrome. Both CJD and fatal insomnia are fully transmissible diseases, a feature that led to the isolation and characterization of different strains of the agent or prion showing distinctive clinical and neuropathological features after transmission to syngenic animals. Here, we review the current knowledge of the effects of the pathogenic mutations linked to genetic CJD and fatal familial insomnia on the prion protein metabolism and physicochemical properties, the disease phenotype and the strain characteristics. The data derived from studies in vitro and from those using cell and animal models are compared with those obtained from the analyses of the naturally occurring disease. The extent of phenotypic variation in genetic prion disease is analyzed in comparison to that of the sporadic disease, which has recently been the topic of a systematic and detailed characterization.


Prion protein Genetic polymorphism Prion protein gene Molecular typing Neurodegeneration Classification 



This study was supported by the University of Bologna (grant RFO) and the Gino Galletti Foundation.


  1. 1.
    Antoine JC, Laplanche JL, Mosnier JF, Beaudry P, Chatelain J, Michel D (1996) Demyelinating peripheral neuropathy with Creutzfeldt–Jakob disease and mutation at codon 200 of the prion protein gene. Neurology 46:1123–1127PubMedGoogle Scholar
  2. 2.
    Apetri AC, Surewicz K, Surewicz WK (2004) The effect of disease-associated mutations on the folding pathway of human prion protein. J Biol Chem 279:18008–18014PubMedCrossRefGoogle Scholar
  3. 3.
    Apetri AC, Vanik DL, Surewicz WK (2005) Polymorphism at residue 129 modulates the conformational conversion of the D178N variant of human prion protein 90–231. Biochemistry 44:15880–15888PubMedCrossRefGoogle Scholar
  4. 4.
    Asante EA, Gowland I, Grimshaw A et al (2009) Absence of spontaneous disease and comparative prion susceptibility of transgenic mice expressing mutant human prion proteins. J Gen Virol 90:546–558PubMedCrossRefGoogle Scholar
  5. 5.
    Ashok A, Hegde RS (2009) Selective processing and metabolism of disease-causing mutant prion proteins. PLoS Pathog 5:e1000479PubMedCrossRefGoogle Scholar
  6. 6.
    Baldin E, Capellari S, Provini F et al (2009) A case of fatal familial insomnia in Africa. J Neurol 256:1778–1779PubMedCrossRefGoogle Scholar
  7. 7.
    Bamdad K, Naderi-Manesh H (2007) Contribution of a putative salt bridge and backbone dynamics in the structural instability of human prion protein upon R208H mutation. Biochem Biophys Res Commun 364:719–724PubMedCrossRefGoogle Scholar
  8. 8.
    Barducci A, Chelli R, Procacci P, Schettino V (2005) Misfolding pathways of the prion protein probed by molecular dynamics simulations. Biophys J 88:1334–1343PubMedCrossRefGoogle Scholar
  9. 9.
    Baron T, Bencsik A, Vulin J et al (2008) A C-terminal protease-resistant prion fragment distinguishes ovine “CH1641-like” scrapie from bovine classical and L-Type BSE in ovine transgenic mice. PLoS Pathog 4:e1000137PubMedCrossRefGoogle Scholar
  10. 10.
    Barron RM, Thomson V, Jamieson E et al (2001) Changing a single amino acid in the N-terminus of murine PrP alters TSE incubation time across three species barriers. EMBO J 20:5070–5078PubMedCrossRefGoogle Scholar
  11. 11.
    Basset-Leobon C, Uro-Coste E, Peoc’h K et al (2006) Familial Creutzfeldt–Jakob disease with an R208H–129V haplotype and kuru plaques. Arch Neurol 63:449–452PubMedCrossRefGoogle Scholar
  12. 12.
    Beck JA, Mead S, Campbell TA et al (2001) Two-octapeptide repeat deletion of prion protein associated with rapidly progressive dementia. Neurology 57:354–356PubMedGoogle Scholar
  13. 13.
    Bessen RA, Marsh RF (1994) Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol 68:7859–7868PubMedGoogle Scholar
  14. 14.
    Bishop MT, Hart P, Aitchison L et al (2006) Predicting susceptibility and incubation time of human-to-human transmission of vCJD. Lancet Neurol 5:393–398PubMedCrossRefGoogle Scholar
  15. 15.
    Bishop MT, Will RG, Manson JC (2010) Defining sporadic Creutzfeldt–Jakob disease strains and their transmission properties. Proc Natl Acad Sci USA 107:12005–12010PubMedCrossRefGoogle Scholar
  16. 16.
    Brown P, Goldfarb LG, Gibbs CJ, Gajdusek DC (1991) The phenotypic expression of different mutations in transmissible familial Creutzfeldt–Jakob disease. Eur J Epidemiol 7:469–476PubMedCrossRefGoogle Scholar
  17. 17.
    Brown P, Goldfarb LG, Kovanen J et al (1992) Phenotypic characteristics of familial Creutzfeldt–Jakob disease associated with the codon 178Asn PRNP mutation. Ann Neurol 31:282–285PubMedCrossRefGoogle Scholar
  18. 18.
    Bruce ME (1993) Scrapie strain variation and mutation. Br Med Bull 49:822–838PubMedGoogle Scholar
  19. 19.
    Bruce ME, Will RG, Ironside JW et al (1997) Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 389:498–501PubMedCrossRefGoogle Scholar
  20. 20.
    Calzolai L, Zahn R (2003) Influence of pH on NMR structure and stability of the human prion protein globular domain. J Biol Chem 278:35592–35596PubMedCrossRefGoogle Scholar
  21. 21.
    Campana V, Sarnataro D, Fasano C, Casanova P, Paladino S, Zurzolo C (2006) Detergent-resistant membrane domains but not the proteasome are involved in the misfolding of a PrP mutant retained in the endoplasmic reticulum. J Cell Sci 119:433–442PubMedCrossRefGoogle Scholar
  22. 22.
    Capellari S, Vital C, Parchi P et al (1997) Familial prion disease with a 144 bp insertion in the prion protein gene in a Basque family. Neurology 49:133–141PubMedGoogle Scholar
  23. 23.
    Capellari S, Zaidi SI, Long AC, Kwon EE, Petersen RB (2000) The thr183ala mutation, not the loss of the first glycosylation site, alters the physical properties of the prion protein. J Alzheimers Dis 2:27–35PubMedGoogle Scholar
  24. 24.
    Capellari S, Parchi P, Russo CM (2000) Effect of the E200K mutation on prion protein metabolism. Comparative study of a cell model and human brain. Am J Pathol 157:613–622PubMedGoogle Scholar
  25. 25.
    Capellari S, Parchi P, Wolff BD et al (2002) Creutzfeldt–Jakob disease associated with a deletion of two repeats in the prion protein gene. Neurology 59:1628–1630PubMedGoogle Scholar
  26. 26.
    Capellari S, Cardone F, Notari S et al (2005) Creutzfeldt–Jakob disease associated with the R208H mutation in the prion protein gene. Neurology 64:905–907PubMedGoogle Scholar
  27. 27.
    Cardone F, Liu QG, Petraroli R et al (1999) Prion protein glycotype analysis in familial and sporadic Creutzfeldt–Jakob disease patients. Brain Res Bull 6:429–433CrossRefGoogle Scholar
  28. 28.
    Caughey B, Race RE, Ernst D, Buchmeier MJ, Chesebro B (1989) Prion protein biosynthesis in scrapie-infected and uninfected neuroblastoma cells. J Virol 63:175–181PubMedGoogle Scholar
  29. 29.
    Chapman J, Ben-Israel J, Goldhammer Y, Korczyn AD (1994) The risk of developing Creutzfeldt–Jakob disease in subjects with the PRNP gene codon 200 point mutation. Neurology 44:1683–1686PubMedGoogle Scholar
  30. 30.
    Chasseigneaux S, Haïk S, Laffont-Proust I et al (2006) V180I mutation of the prion protein gene associated with atypical PrPSc glycosylation. Neurosci Lett 408:165–169PubMedCrossRefGoogle Scholar
  31. 31.
    Chen SG, Parchi P, Brown P et al (1997) Allelic origin of the abnormal prion proteins in familial prion diseases. Nat Med 3:1009–1015PubMedCrossRefGoogle Scholar
  32. 32.
    Chesebro B (2003) Introduction to the transmissible spongiform encephalopathies or prion diseases. Br Med Bull 66:1–20PubMedCrossRefGoogle Scholar
  33. 33.
    Chiesa R, Piccardo P, Ghetti B, Harris DA (1998) Neurological illness in transgenic mice expressing a prion protein with an insertional mutation. Neuron 21:1339–1351PubMedCrossRefGoogle Scholar
  34. 34.
    Chiesa R, Pestronk A, Schmidt RE et al (2001) Primary myopathy and accumulation of PrPSc-like molecules in peripheral tissues of transgenic mice expressing a prion protein insertional mutation. Neurobiol Dis 8:279–288PubMedCrossRefGoogle Scholar
  35. 35.
    Chiti F, Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75:333–366PubMedCrossRefGoogle Scholar
  36. 36.
    Choi CJ, Kanthasamy A, Anantharam V, Kanthasamy AG (2006) Interaction of metals with prion protein: possible role of divalent cations in the pathogenesis of prion diseases. Neurotoxicology 27:777–787PubMedCrossRefGoogle Scholar
  37. 37.
    Clerici F, Elia A, Girotti F et al (2008) Atypical presentation of CJD: the first Italian case associated with E196K mutation in the PRNP gene. J Neurol Sci 275:145–147PubMedCrossRefGoogle Scholar
  38. 38.
    Cochran EJ, Bennett DA, Cervenakova L et al (1996) Familial Creutzfeldt–Jakob disease with a five-repeat octapeptide insert mutation. Neurology 47:727–733PubMedGoogle Scholar
  39. 39.
    Cohen FE, Pan KM, Huang Z, Baldwin M, Fletterick RJ, Prusiner SB (1994) Structural clues to prion replication. Science 264:530–531PubMedCrossRefGoogle Scholar
  40. 40.
    Collins S, Boyd A, Fletcher A et al (2000) Novel prion protein gene mutation in an octogenarian with CJD. Arch Neurol 57:1058–1063PubMedCrossRefGoogle Scholar
  41. 41.
    D’Alessandro M, Petraroli R, Ladogana A, Pocchiari M (1998) High incidence of Creutzfeldt–Jakob disease in rural Calabria, Italy. Lancet 352:1989–1990PubMedCrossRefGoogle Scholar
  42. 42.
    Dossena S, Imeri L, Mangieri M et al (2008) Mutant prion protein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model. Neuron 60:598–609PubMedCrossRefGoogle Scholar
  43. 43.
    Drisaldi B, Stewart RS, Adles C et al (2003) Mutant PrP is delayed in its exit from the endoplasmic reticulum, but neither wild-type nor mutant PrP undergoes retrotranslocation prior to proteasomal degradation. J Biol Chem 278:21732–21743PubMedCrossRefGoogle Scholar
  44. 44.
    Endo T, Groth D, Prusiner SB, Kobata A (1989) Diversity of oligosaccharide structures linked to asparagines of the scrapie prion protein. Biochemistry 28:8380–8388PubMedCrossRefGoogle Scholar
  45. 45.
    Gabizon R, Rosenmann H, Meiner Z et al (1993) Mutation and polymorphism of the prion protein gene in Libyan Jews with Creutzfeldt–Jakob disease. Am J Hum Genet 53:828–835PubMedGoogle Scholar
  46. 46.
    Gabizon R, Telling G, Meiner Z, Halimi M, Kahana I, Prusiner SB (1996) Insoluble wild-type and protease-resistant mutant prion protein in brains of patients with inherited prion diseases. Nat Med 2:59–64PubMedCrossRefGoogle Scholar
  47. 47.
    Gambetti P, Parchi P, Petersen RB, Chen SG, Lugaresi E (1995) Fatal familial insomnia and familial Creutzfeldt–Jakob disease: clinical, pathological and molecular features. Brain Pathol 5:43–51PubMedCrossRefGoogle Scholar
  48. 48.
    Garcin R, Brion S, Khochneviss AA (1963) Le syndrome de Creutzfeldt–Jakob et les syndromes corticotries du presenium (a l’occasion de observations anatomo-cliniques). Rev Neurol (Paris) 109:419–441Google Scholar
  49. 49.
    Gelpi E, Kovacs GG, Ströbel T et al (2005) Prion disease with a 144 base pair insertion: unusual cerebellar prion protein immunoreactivity. Acta Neuropathol 110:513–519PubMedCrossRefGoogle Scholar
  50. 50.
    Goldfarb LG, Mitrová E, Brown P, Toh BK, Gajdusek DC (1990) Mutation in codon 200 of scrapie amyloid protein gene in two clusters of Creutzfeldt–Jakob disease in Slovakia. Lancet 336:514–515PubMedCrossRefGoogle Scholar
  51. 51.
    Goldfarb LG, Brown P, McCombie WR et al (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 88:10926–10930PubMedCrossRefGoogle Scholar
  52. 52.
    Goldfarb LG, Brown P, Little BW et al (1993) A new (two-repeat) octapeptide coding insert mutation in Creutzfeldt–Jakob disease. Neurology 43:2392–2394PubMedGoogle Scholar
  53. 53.
    Goldfarb LG, Petersen RB, Tabaton M et al (1992) Fatal familial insomnia and familial Creutzfeldt Jakob disease: disease phenotype determined by a DNA polymorphism. Science 258:806–808PubMedCrossRefGoogle Scholar
  54. 54.
    Goldgaber D, Goldfarb LG, Brown P et al (1989) Mutations in familial Creutzfeldt–Jakob disease and Gerstmann-Sträussler-Scheinker’s syndrome. Exp Neurol 106:204–206PubMedCrossRefGoogle Scholar
  55. 55.
    Grasbon-Frodl E, Lorenz H, Mann U, Nitsch RM, Windl O, Kretzschmar HA (2004) Loss of glycosylation associated with the T183A mutation in human prion disease. Acta Neuropathol 108:476–484PubMedCrossRefGoogle Scholar
  56. 56.
    Hama T, Iwasaki Y, Niwa H et al (2009) An autopsied case of panencephalopathic-type Creutzfeldt–Jakob disease with mutation in the prion protein gene at codon 232 and type 1 prion protein. Neuropathology 296:727–734CrossRefGoogle Scholar
  57. 57.
    Hainfellner JA, Parchi P, Kitamoto T, Jarius C, Gambetti P, Budka H (1999) A novel phenotype in familial Creutzfeldt–Jakob disease: prion protein gene E200K mutation coupled with valine at codon 129 and type 2 protease-resistant prion protein. Ann Neurol 45:812–816PubMedCrossRefGoogle Scholar
  58. 58.
    Hill AF, Joiner S, Beck JA et al (2006) Distinct glycoform ratios of protease resistant prion protein associated with PRNP point mutations. Brain 129:676–685PubMedCrossRefGoogle Scholar
  59. 59.
    Hsiao KK, Scott M, Foster D, Groth DF, DeArmond SJ, Prusiner SB (1990) Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science 250:1587–1590PubMedCrossRefGoogle Scholar
  60. 60.
    Hsiao KK, Groth D, Scott M et al (1994) Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein. Proc Natl Acad Sci USA 91:9126–9130PubMedCrossRefGoogle Scholar
  61. 61.
    Huang Z, Gabriel JM, Baldwin MA, Fletterick RJ, Prusiner SB, Cohen FE (1994) Proposed three-dimensional structure for the cellular prion protein. Proc Natl Acad Sci USA 91:7139–7143PubMedCrossRefGoogle Scholar
  62. 62.
    Ivanova L, Barmada S, Kummer T, Harris DA (2001) Mutant prion proteins are partially retained in the endoplasmic reticulum. J Biol Chem 276:42409–42421PubMedCrossRefGoogle Scholar
  63. 63.
    Jackson WS, Borkowski AW, Faas H et al (2009) Spontaneous generation of prion infectivity in fatal familial insomnia knocking mice. Neuron 63:438–450PubMedCrossRefGoogle Scholar
  64. 64.
    Jacob H, Pyrkosch W, Strube H (1950) The hereditary form of Creutzfeldt–Jakob disease (the Backer family). Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr 184:653–674PubMedGoogle Scholar
  65. 65.
    Jansen C, van Swieten JC, Capellari S et al (2009) Inherited Creutzfeldt–Jakob disease in a Dutch patient with a novel five octapeptide repeat insertion and unusual cerebellar morphology. J Neurol Neurosurg Psychiatry 80:1386–1389PubMedCrossRefGoogle Scholar
  66. 66.
    Jarius C, Kovacs GG, Belay G, Hainfellner JA, Mitrova E, Budka H (2003) Distinctive cerebellar immunoreactivity for the prion protein in familial (E200K) Creutzfeldt–Jakob disease. Acta Neuropathol 105:49–54Google Scholar
  67. 67.
    Jin K, Shiga Y, Shibuya S et al (2004) Clinical features of Creutzfeldt–Jakob disease with V180I mutation. Neurology 62:502–505PubMedGoogle Scholar
  68. 68.
    Kahana E, Zilber N, Abraham M (1991) Do Creutzfeldt–Jakob disease patients of Jewish Libyan origin have unique clinical features? Neurology 41:1390–1392PubMedGoogle Scholar
  69. 69.
    Kalastavadi T, True HL (2008) Prion protein insertional mutations increase aggregation propensity but not fiber stability. BMC Biochem 9:7PubMedCrossRefGoogle Scholar
  70. 70.
    Kascsak RJ, Rubenstein R, Merz PA et al (1986) Immunological comparison of scrapie-associated fibrils isolated from animals infected with four different scrapie strains. J Virol 59:676–683PubMedGoogle Scholar
  71. 71.
    Kiachopoulos S, Bracher A, Winklhofer KF, Tatzelt J (2005) Pathogenic mutations located in the hydrophobic core of the prion protein interfere with folding and attachment of the glycosylphosphatidylinositol anchor. J Biol Chem 280:9320–9329PubMedCrossRefGoogle Scholar
  72. 72.
    Kirschbaum WR (1924) Zwei eigenartige Erkrankung des Zentralnervensystems nach Art der spatischen Pseudosklerose (Jakob). Z Neurol Pyschiatry 92:175–220CrossRefGoogle Scholar
  73. 73.
    Kobayashi A, Sakuma N, Matsuura Y, Mohri S, Aguzzi A, Kitamoto T (2010) Experimental verification of a traceback phenomenon in prion infection. J Virol 84:3230–3238PubMedCrossRefGoogle Scholar
  74. 74.
    Kong Q, Surewicz WK, Petersen RB et al (2003) Inherited prion diseases. In: Prusiner SB (ed) Prion biology disease. Cold Spring Harbor Laboratory Press, New York, pp 673–775Google Scholar
  75. 75.
    Kovács GG, Trabattoni G, Hainfellner JA, Ironside JW, Knight RS, Budka H (2002) Mutations of the prion protein gene phenotypic spectrum. J Neurol 249:1567–1582PubMedCrossRefGoogle Scholar
  76. 76.
    Kovács GG, Puopolo M, Ladogana A et al (2005) Genetic prion disease: the EUROCJD experience. Hum Genet 118:166–174PubMedCrossRefGoogle Scholar
  77. 77.
    Krasnianski A, Bartl M, Sanchez Juan PJ et al (2008) Fatal familial insomnia: clinical features and early identification. Ann Neurol 63:658–661PubMedCrossRefGoogle Scholar
  78. 78.
    Krebs B, Lederer RM, Windl O, Grasbon-Frodl EM, Zerr I, Kretzschmar HA (2005) Creutzfeldt–Jakob disease associated with an R148H mutation of the prion protein gene. Neurogenetics 6:97–100PubMedCrossRefGoogle Scholar
  79. 79.
    Kretzschmar HA, Stowring LE, Westaway D, Stubblebine WH, Prusiner SB, Dearmond SJ (1986) Molecular cloning of a human prion protein cDNA. DNA 5:315–324PubMedGoogle Scholar
  80. 80.
    Kretzschmar HA, Neumann M, Stavrou D (1995) Codon 178 mutation of the human prion protein gene in a German family (Backer family): sequencing data from 72-year old celloidin-embedded brain tissue. Acta Neuropathol 89:96–98PubMedCrossRefGoogle Scholar
  81. 81.
    Ladogana A, Almonti S, Petraroli R et al (2001) Mutation of the PRNP gene at codon 211 in familial Creutzfeldt–Jakob disease. Am J Med Genet 103:133–137PubMedCrossRefGoogle Scholar
  82. 82.
    Ladogana A, Puopolo M, Poleggi A et al (2005) High incidence of genetic human transmissible spongiform encephalopathies in Italy. Neurology 64:1592–1597PubMedCrossRefGoogle Scholar
  83. 83.
    Langella E, Improta R, Crescenzi O, Barone V (2006) Assessing the acid-base and conformational properties of histidine residues in human prion protein (125–228) by means of pK(a) calculations and molecular dynamics simulations. Proteins 64:167–177PubMedCrossRefGoogle Scholar
  84. 84.
    Laplanche JL, Delasnerie-Laupretre N, Brandel JP et al (1994) Molecular genetics of prion diseases in France. Neurology 44:2347–2351PubMedGoogle Scholar
  85. 85.
    Lehmann S, Harris DA (1996) Mutant and infectious prion proteins display common biochemical properties in cultured cells. J Biol Chem 271:1633–1637PubMedCrossRefGoogle Scholar
  86. 86.
    Lehmann S, Harris DA (1996) Two mutant prion proteins expressed in cultured cells acquire biochemical properties reminiscent of the scrapie isoform. Proc Natl Acad Sci 93:5610–5614PubMedCrossRefGoogle Scholar
  87. 87.
    Leliveld SR, Stitz L, Korth C (2008) Expansion of the octarepeat domain alters the misfolding pathway but not the folding pathway of the prion protein. Biochemistry 47:6267–6278PubMedCrossRefGoogle Scholar
  88. 88.
    Lewis PA, Tattum MH, Jones S et al (2006) Codon 129 polymorphism of the human prion protein influences the kinetics of amyloid formation. J Gen Virol 87:2443–2449PubMedCrossRefGoogle Scholar
  89. 89.
    Liemann S, Glockshuber R (1999) Influence of amino acid substitutions related to inherited human prion diseases on the thermodynamic stability of the cellular prion protein. Biochemistry 38:3258–3267PubMedCrossRefGoogle Scholar
  90. 90.
    Little BW, Brown PW, Rodgers-Johnson P, Perl DP, Gajdusek DC (1986) Familial myoclonic dementia masquerading as Creutzfeldt–Jakob disease. Ann Neurol 20:231–239PubMedCrossRefGoogle Scholar
  91. 91.
    Liu Z, Jia L, Piao Y et al. (2009) Creutzfeldt–Jakob disease with PRNP G114V mutation in a Chinese family. Acta Neurol Scand (epub ahead of print)Google Scholar
  92. 92.
    Lorenz H, Windl O, Kretzschmar HA (2002) Cellular phenotyping of secretory and nuclear prion proteins associated with inherited prion diseases. J Biol Chem 277:8508–8516PubMedCrossRefGoogle Scholar
  93. 93.
    Lugaresi E, Medori R, Montagna P et al (1986) Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 315:997–1003PubMedCrossRefGoogle Scholar
  94. 94.
    Ma J, Lindquist S (2001) Wild-type PrP and a mutant associated with prion disease are subject to retrograde transport and proteasome degradation. Proc Natl Acad Sci 98:14955–14960PubMedCrossRefGoogle Scholar
  95. 95.
    Manetto V, Medori R, Cortelli P et al (1992) Fatal familial insomnia: clinical and pathologic study of five new cases. Neurology 42:312–319PubMedGoogle Scholar
  96. 96.
    Manson JC, Jamieson E, Baybutt H et al (1999) A single amino acid alteration (101L) introduced into murine PrP dramatically alters incubation time of transmissible spongiform encephalopathy. EMBO J 18:6855–6864PubMedCrossRefGoogle Scholar
  97. 97.
    Martin JJ, Yap M, Nei IP, Tan TE (1983) Selective thalamic degeneration: report of a case with memory and mental disturbances. Clin Neuropathol 2:156–162PubMedGoogle Scholar
  98. 98.
    Massignan T, Biasini E, Lauranzano E et al (2010) Mutant prion protein expression is associated with an alteration of the Rab GDP dissociation inhibitor alpha (GDI)/Rab11 pathway. Mol Cell Proteomics 9:611–622PubMedCrossRefGoogle Scholar
  99. 99.
    Mastrianni JA, Iannicola C, Myers RM, DeArmond S, Prusiner SB (1996) Mutation of the prion protein gene at codon 208 in familial Creutzfeldt–Jakob disease. Neurology 47:1305–1312PubMedGoogle Scholar
  100. 100.
    Mastrianni J, Nixon R, Layzer R et al (1999) Prion protein conformation in a patient with sporadic fatal insomnia. N Engl J Med 340:1630–1638PubMedCrossRefGoogle Scholar
  101. 101.
    Mastrianni JA, Capellari S, Telling GC et al (2001) Inherited prion disease caused by the V210I mutation: transmission to transgenic mice. Neurology 57:2198–2205PubMedGoogle Scholar
  102. 102.
    Mead S, Poulter M, Beck J et al (2006) Inherited prion disease with six octapeptide repeat insertional mutation-molecular analysis of phenotypic heterogeneity. Brain 129:2297–2317PubMedCrossRefGoogle Scholar
  103. 103.
    Mead S, Webb TEF, Campbell TA et al (2007) Inherited prion disease with 5-OPRI. Neurology 69:730–738PubMedCrossRefGoogle Scholar
  104. 104.
    Medori R, Tritschler HJ, LeBlanc A et al (1992) Fatal familial insomnia is a prion disease with a mutation at codon 178 of the prion gene. N Engl J Med 326:444–449PubMedCrossRefGoogle Scholar
  105. 105.
    Meggendorfer F (1930) Klinische und genealogische Beobachtungen bein einem Fall von spastischen Pseudokosklerose Jakobs. Z Neurol Psychiatry 128:337–341CrossRefGoogle Scholar
  106. 106.
    Mitrova E, Belay G (2002) Creutzfeldt–Jakob disease with E200K mutation in Slovakia: characterization and development. Acta Virol 46:31–39PubMedGoogle Scholar
  107. 107.
    Miyakawa T, Inoue K, Iseki E et al (1998) Japanese Creutzfeldt–Jakob disease patients exhibiting high incidence of the E200K PRNP mutation and located in the basin of a river. Neurol Res 20:684–688PubMedGoogle Scholar
  108. 108.
    Monari L, Chen SC, Brown P et al (1994) Fatal familial insomnia and familial Creutzfeldt–Jakob disease: different prion proteins determined by a DNA polymorphism. Proc Natl Acad Sci USA 91:2839–2842PubMedCrossRefGoogle Scholar
  109. 109.
    Montagna P, Gambetti P, Cortelli P, Lugaresi E (2003) Familial and sporadic fatal insomnia. Lancet Neurol 2:167–176PubMedCrossRefGoogle Scholar
  110. 110.
    Neufeld MY, Josiphov J, Korczyn AD (1992) Demyelinating peripheral neuropathy in Creutzfeldt–Jakob disease. Muscle Nerve 15:1234–1239PubMedCrossRefGoogle Scholar
  111. 111.
    Nicolas O, Gavín R, del Río JA (2009) New insights into cellular prion protein (PrPc) functions: the “ying and yang” of a relevant protein. Brain Res Rev 61:170–184PubMedCrossRefGoogle Scholar
  112. 112.
    Nitrini R, Rosemberg S, Passos-Bueno MR et al (1997) Familial spongiform encephalopathy with distinct clinico-pathological features associated with a novel prion gene mutation at codon 183. Ann Neurol 42:138–146PubMedCrossRefGoogle Scholar
  113. 113.
    Nonno R, Di Bari M, Cardone F et al (2006) Efficient transmission and characterization of Creutzfeldt–Jakob disease strains in bank voles. PLoS Pathog 2:e12PubMedCrossRefGoogle Scholar
  114. 114.
    Notari S, Capellari S, Giese A et al (2004) Effects of different experimental conditions on the PrPSc core generated by protease digestion: implications for strain typing and molecular classification of CJD. J Biol Chem 279:16797–16804PubMedCrossRefGoogle Scholar
  115. 115.
    Notari S, Strammiello R, Capellari S et al (2008) Characterization of truncated forms of abnormal prion protein in Creutzfeldt–Jakob disease. J Biol Chem 283:30557–30565PubMedCrossRefGoogle Scholar
  116. 116.
    Oda M (1976) Thalamus degeneration in Japan: a review from clinical and pathological veiwpoints. Appl Neurophysiol 39:178–198PubMedGoogle Scholar
  117. 117.
    Owen F, Poulter M, Lofthouse R et al (1989) Insertion in prion protein gene in familial Creutzfeldt–Jakob disease. Lancet 7:51–52CrossRefGoogle Scholar
  118. 118.
    Palmer MS, Dryden AJ, Hughes JT, Collinge J (1991) Homozygous prion protein genotype predisposes to sporadic Creutzfeldt–Jakob disease. Nature 352:340–342PubMedCrossRefGoogle Scholar
  119. 119.
    Parchi P, Castellani R, Cortelli P et al (1995) Regional distribution of protease-resistant prion protein in fatal familial insomnia. Ann Neurol 38:21–29PubMedCrossRefGoogle Scholar
  120. 120.
    Parchi P, Castellani R, Capellari S et al (1996) Molecular basis of phenotypic variability in sporadic Creutzfeldt–Jakob disease. Ann Neurol 39:767–778PubMedCrossRefGoogle Scholar
  121. 121.
    Parchi P, Capellari S, Chen SG et al (1997) Typing prion isoforms. Nature 386:232–234PubMedCrossRefGoogle Scholar
  122. 122.
    Parchi P, Petersen RB, Chen SG et al (1998) Molecular pathology of fatal familial insomnia. Brain Pathol 8:539–548PubMedCrossRefGoogle Scholar
  123. 123.
    Parchi P, Giese A, Capellari S et al (1999) Classification of sporadic Creutzfeldt–Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46:224–233PubMedCrossRefGoogle Scholar
  124. 124.
    Parchi P, Capellari S, Chin S et al (1999) A sporadic prion disease mimicking fatal familial insomnia. Neurology 52:1757–1763PubMedGoogle Scholar
  125. 125.
    Parchi P, Zou W, Wang W et al (2000) Genetic influence on the structural variations of the abnormal prion protein. Proc Natl Acad Sci USA 97:10168–10171PubMedCrossRefGoogle Scholar
  126. 126.
    Parchi P, Strammiello R, Notari S et al (2009) Incidence and spectrum of sporadic Creutzfeldt–Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification. Acta Neuropathol 118:659–671PubMedCrossRefGoogle Scholar
  127. 127.
    Parchi P, Notari S, Weber P et al (2009) Inter-laboratory assessment of PrPSc typing in Creutzfeldt–Jakob disease: a western blot study within the NeuroPrion Consortium. Brain Pathol 19:384–391PubMedCrossRefGoogle Scholar
  128. 128.
    Parchi P, Cescatti M, Notari S et al. (2010) Agent strain variation in human prion disease: insights from a molecular and pathological revision of the NIH series of experimentally transmitted disease. Brain 133:3030–3042Google Scholar
  129. 129.
    Pastore M, Chin SS, Bell KL et al (2005) Creutzfeldt–Jakob disease (CJD) with a mutation at codon 148 of prion protein gene: relationship with sporadic CJD. Am J Pathol 167:1729–1738PubMedGoogle Scholar
  130. 130.
    Peoc’h K, Manivet P, Beaudry P et al (2000) Identification of three novel mutations (E196K, V203I, E211Q) in the prion protein gene (PRNP) in inherited prion diseases with Creutzfeldt–Jakob disease phenotype. Hum Mutat 5:482CrossRefGoogle Scholar
  131. 131.
    Petersen RB, Tabaton M, Berg L et al (1992) Analysis of the prion gene in thalamic dementia. Neurology 42:1859–1863PubMedGoogle Scholar
  132. 132.
    Petersen RB, Parchi P, Richardson SL, Urig CB, Gambetti P (1996) Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of the prion protein. J Biol Chem 271:12661–12668PubMedCrossRefGoogle Scholar
  133. 133.
    Pocchiari M, Salvatore M, Cutruzzola F et al (1993) A new point mutation of the prion protein gene in Creutzfeldt–Jakob disease. Ann Neurol 34:802–807PubMedCrossRefGoogle Scholar
  134. 134.
    Priola SA, Chesebro B (1998) Abnormal properties of prion protein with insertional mutations in different cell types. J Biol Chem 273:11980–11985PubMedCrossRefGoogle Scholar
  135. 135.
    Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363–13383PubMedCrossRefGoogle Scholar
  136. 136.
    Puckett C, Concannon P, Casey C, Hood L (1991) Genomic structure of human prion protein gene. Am J Genet 49:320–329Google Scholar
  137. 137.
    Puoti G, Rossi G, Giaccone G et al (2000) Polymorphism at codon 129 of PRNP affects the phenotypic expression of Creutzfeldt–Jakob disease linked to the E200K mutation. Ann Neurol 48:269–270PubMedCrossRefGoogle Scholar
  138. 138.
    Riek R, Wider G, Billeter M, Hornemann S, Glockshuber R, Wüthrich K (1998) Prion protein NMR structure and familial human spongiform encephalopathies. Proc Natl Acad Sci 95:11667–11672PubMedCrossRefGoogle Scholar
  139. 139.
    Ripoll L, Laplanche JL, Salzmann M et al (1993) A new point mutation in the prion protein gene at codon 210 in Creutzfeldt–Jakob disease. Neurology 43:1934–1938PubMedGoogle Scholar
  140. 140.
    Rodriguez MM, Peoc’h K, Haïk S et al (2005) A novel mutation (G114V) in the prion protein gene in a family with inherited prion disease. Neurology 64:1455–1457PubMedGoogle Scholar
  141. 141.
    Rodríguez-Martínez AB, Barreau C, Coupry I et al (2005) Ancestral origins of the prion protein gene D178N mutation in the Basque Country. Hum Genet 117:61–69PubMedCrossRefGoogle Scholar
  142. 142.
    Roeber S, Krebs B, Neumann M et al (2005) Creutzfeldt–Jakob disease in a patient with an R208H mutation of the prion protein gene (PRNP) and a 17-kDa prion protein fragment. Acta Neuropathol 109:443–448PubMedCrossRefGoogle Scholar
  143. 143.
    Roeber S, Grasbon-Frodl EM, Windl O et al (2008) Evidence for a pathogenic role of different mutations at codon 188 of PRNP. PLoS One 3:e2147PubMedCrossRefGoogle Scholar
  144. 144.
    Rogers M, Taraboulos A, Scott M, Groth D, Prusiner SB (1990) Intracellular accumulation of the cellular prion protein after mutagenesis of its Asn-linked glycosylation sites. Glycobiology 1:101–109PubMedCrossRefGoogle Scholar
  145. 145.
    Roos R, Gajdusek DC, Gibbs CJ (1973) The clinical characteristics of transmissible Creutzfeldt–Jacob disease. Brain 96:1–20PubMedCrossRefGoogle Scholar
  146. 146.
    Rosenmann H, Talmor G, Halimi M, Yanai A, Gabizon R, Meiner Z (2001) Prion protein with an E200K mutation displays properties similar to those of the cellular isoform PrP(C). J Neurochem 76:1654–1662PubMedCrossRefGoogle Scholar
  147. 147.
    Schiff E, Campana V, Tivodar S, Lebreton S, Gousset K, Zurzolo C (2008) Coexpression of wild-type and mutant prion proteins alters their cellular localization and partitioning into detergent-resistant membranes. Traffic 9:1101–1115PubMedCrossRefGoogle Scholar
  148. 148.
    Schulman S (1957) Bilateral symmetrical degeneration of the thalamus: a clinico-pathological study. J Neuropathol Exp Neurol 16:446–470PubMedCrossRefGoogle Scholar
  149. 149.
    Shimizu H, Yamada M, Matsubara N et al (2009) Creutzfeldt–Jakob disease with an M232R substitution: report of a patient showing slowly progressive disease with abundant plaque-like PrP deposits in the cerebellum. Neuropathology 29:735–743PubMedCrossRefGoogle Scholar
  150. 150.
    Skworc KH, Windl O, Schulz-Schaeffer WJ et al (1999) Familial Creutzfeldt–Jakob disease with a novel 120-bp insertion in the prion protein gene. Ann Neurol 46:693–700CrossRefGoogle Scholar
  151. 151.
    Silvestrini MC, Cardone F, Maras B et al (1997) Identification of the prion protein allotypes which accumulate in the brain of sporadic and familial Creutzfeldt–Jakob disease patients. Nat Med 3:521–525PubMedCrossRefGoogle Scholar
  152. 152.
    Soldevila M, Calafell F, Andrés AM et al (2003) Prion susceptibility and protective alleles exhibit marked geographic differences. Hum Mutat 22:104–105PubMedCrossRefGoogle Scholar
  153. 153.
    Stahl N, Baldwin MA, Burlingame AL, Prusiner SB (1990) Identification of glycoinositol phospholipid linked and truncated forms of the scrapie prion protein. Biochemistry 29:8879–8884PubMedCrossRefGoogle Scholar
  154. 154.
    Stern K (1939) Severe dementia associated with bilateral symmetrical degeneration of the thalamus. Brain 62:157–171CrossRefGoogle Scholar
  155. 155.
    Swietnicki W, Petersen SB, Gambetti P, Surewicz WK (1998) Familial mutations and the thermodynamic stability of the recombinant human prion protein. J Biol Chem 273:31048–31052PubMedCrossRefGoogle Scholar
  156. 156.
    Tateishi J, Brown P, Kitamoto T et al (1995) First experimental transmission of fatal familial insomnia. Nature 376:434–435PubMedCrossRefGoogle Scholar
  157. 157.
    Telling GC, Parchi P, DeArmond SJ et al (1996) Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274:2079–2082PubMedCrossRefGoogle Scholar
  158. 158.
    Vetrugno V, Malchow M, Liu Q, Marziali G, Battistini A, Pocchiari M (1999) Expression of wild-type and V210I mutant prion protein in human neuroblastoma cells. Neurosci Lett 270:41–44PubMedCrossRefGoogle Scholar
  159. 159.
    Watanabe Y, Hiraoka W, Shimoyama Y, Horiuchi M, Kuwabara M, Inanami O (2008) Instability of familial spongiform encephalopathy-related prion mutants. Biochem Biophys Res Commun 366:244–249PubMedCrossRefGoogle Scholar
  160. 160.
    Weissmann C, Flechsig E (2003) PrP knock-out and PrP transgenic mice in prion research. Br Med Bull 66:43–60PubMedCrossRefGoogle Scholar
  161. 161.
    Windl O, Dempster M, Estibeiro JP et al (1996) Genetic basis of Creutzfeldt–Jakob disease in the United Kingdom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene. Hum Genet 98:259–264PubMedCrossRefGoogle Scholar
  162. 162.
    Ye J, Han J, Shi Q et al (2008) Human prion disease with a G114V mutation and epidemiological studies in a Chinese family: a case series. J Med Case Reports 2:331PubMedCrossRefGoogle Scholar
  163. 163.
    Yoshida H, Terada S, Ishizu H et al (2010) An autopsy case of Creutzfeldt–Jakob disease with a V180I mutation of the PrP gene and Alzheimer-type pathology. Neuropathology 30:159–164PubMedCrossRefGoogle Scholar
  164. 164.
    Zahn R, Liu A, Luhrs T, Riek R et al (2000) NMR solution structure of the human prion protein. Proc Natl Acad Sci USA 97:145–150PubMedCrossRefGoogle Scholar
  165. 165.
    Zhang Y, Swietnicki W, Zagorski MG, Surewicz WK, Sonnichsen FD (2000) Solution structure of the E200K variant of human prion protein. J Biol Chem 275:33650–33654PubMedCrossRefGoogle Scholar
  166. 166.
    Zou WQ, Capellari S, Parchi P, Sy MS, Gambetti P, Chen SG (2003) Identification of novel proteinase K-resistant C-terminal fragments of PrP in Creutzfeldt–Jakob disease. J Biol Chem 278:40429–40436PubMedCrossRefGoogle Scholar
  167. 167.
    Zuegg J, Gready JE (1999) Molecular dynamics simulations of human prion protein: importance of correct treatment of electrostatic interactions. Biochemistry 38:13862–13876PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Sabina Capellari
    • 1
  • Rosaria Strammiello
    • 1
  • Daniela Saverioni
    • 1
  • Hans Kretzschmar
    • 2
  • Piero Parchi
    • 1
    Email author
  1. 1.Department of Neurological SciencesUniversity of BolognaBolognaItaly
  2. 2.Institut für Neuropathologie Ludwig-Maximilians-Universität MünchenMunichGermany

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