PrionDB: Extraction of mutation data from the literature

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This data was extracted from Medline abstracts and full texts (when available) in an automated manner.

The table below describes different point mutations at a given position and provides links to other documents. The sentence(s) where the point mutations in PRIO_HUMAN at position 200 were found are listed after the table.

Point mutations at position E200 in PRIO_HUMAN

ProteinPRIO_HUMAN (P04156)    Gene: PRNP    (other point mutations)Swiss-Prot
Cross-reference table
Family page
PositionE200
General numbering (PrionDB) -
DomainNot determined
Family alignments Mammalian prion proteins
Prion proteins (PRP, PRNP)
Other point mutations at the same position Position 200 in Mammalian prion proteins family
Position 200 in Prion proteins (PRP, PRNP) family
Reference #1Parchi P, Capellari S, Chin S, Schwarz HB, Schecter NP, Butts JD, Hudkins P, Burns DK, Powers JM, Gambetti P
Neurology 1999 Jun 10;52(9):1757-63.		Medline
Text sourceHTML full text
Point mutationE200K (True positive)
Reference #2Narwa R, Harris DA
Biochemistry 1999 Jul 6;38(27):8770-7.		Medline
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Point mutationE200K (True positive)
Reference #3Cardone F, Liu QG, Petraroli R, Ladogana A, D'Alessandro M, Arpino C, Di Bari M, Macchi G, Pocchiari M
Brain Res Bull 1999 Aug;49(6):429-33.		Medline
Text sourceabstract
Point mutationE200K (True positive)
Cited point mutationGlu200Lys
Reference #4Mallucci GR, Campbell TA, Dickinson A, Beck J, Holt M, Plant G, de Pauw KW, Hakin RN, Clarke CE, Howell S, Davies-Jones GA, Lawden M, Smith CM, Ince P, Ironside JW, Bridges LR, Dean A, Weeks I, Collinge J
Brain 1999 Oct;122 ( Pt 10):1823-37.		Medline
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Point mutationE200K (True positive)
Reference #5Rosenmann H, Kahana E, Korczyn AD, Kahana I, Chapman J, Gabizon R
Neurology 1999 Oct 12;53(6):1328-9.		Medline
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Point mutationE200K (True positive)
Reference #6Zuegg J, Gready JE
Biochemistry 1999 Oct 19;38(42):13862-76.		Medline
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Point mutationE200K (True positive)
Reference #7Laplanche JL, Hachimi KH, Durieux I, Thuillet P, Defebvre L, Delasnerie-Laupretre N, Peoc'h K, Foncin JF, Destee A
Brain 1999 Dec;122 ( Pt 12):2375-86.		Medline
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Point mutationE200K (True positive)
Reference #8Simon ES, Kahana E, Chapman J, Treves TA, Gabizon R, Rosenmann H, Zilber N, Korczyn AD
Ann Neurol 2000 Feb;47(2):257-60.		Medline
Text sourceabstract
Point mutationE200K (True positive)
Reference #9Mitrova E, Belay G
Bratisl Lek Listy 1999 Apr;100(4):187-91.		Medline
Text sourceabstract
Point mutationE200K (True positive)
Reference #10Capellari S, Parchi P, Russo CM, Sanford J, Sy MS, Gambetti P, Petersen RB
Am J Pathol 2000 Aug;157(2):613-22.		Medline
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Point mutationE200K (True positive)
Reference #11Stewart RS, Harris DA
J Biol Chem 2001 Jan 19;276(3):2212-20.		Medline
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Point mutationE200K (Not yet checked)
Reference #12Tagliavini F, Lievens PM, Tranchant C, Warter JM, Mohr M, Giaccone G, Perini F, Rossi G, Salmona M, Piccardo P, Ghetti B, Beavis RC, Bugiani O, Frangione B, Prelli F
J Biol Chem 2001 Feb 23;276(8):6009-15.		Medline
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Point mutationE200K (True positive)
Reference #13Rosenmann H, Talmor G, Halimi M, Yanai A, Gabizon R, Meiner Z
J Neurochem 2001 Mar;76(6):1654-62.		Medline
Text sourceabstract
Point mutationE200K (True positive)
Reference #14Negro A, Ballarin C, Bertoli A, Massimino ML, Sorgato MC
Mol Cell Neurosci 2001 Mar;17(3):521-38.		Medline
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Point mutationE200K (Not yet checked)
Reference #15Thompson AJ, Barnham KJ, Norton RS, Barrow CJ
Biochim Biophys Acta 2001 Jan 12;1544(1-2):242-54.		Medline
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Point mutationE200K (Not yet checked)
Cited point mutationGlu200Lys,Glu-200-Lys
Reference #16Ivanova L, Barmada S, Kummer T, Harris DA
J Biol Chem 2001 Nov 9;276(45):42409-21.		Medline
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Point mutationE200K (Not yet checked)
Reference #17Daniels M, Cereghetti GM, Brown DR
Eur J Biochem 2001 Dec;268(23):6155-64.		Medline
Text sourceabstract
Point mutationE200K (True positive)
Reference #18Lorenz H, Windl O, Kretzschmar HA
J Biol Chem 2002 Mar 8;277(10):8508-16.		Medline
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Point mutationE200K (True positive)
Reference #19Mastrianni JA, Capellari S, Telling GC, Han D, Bosque P, Prusiner SB, DeArmond SJ
Neurology 2001 Dec 26;57(12):2198-205.		Medline
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Point mutationE200K (True positive)
Reference #20Mahfoud R, Garmy N, Maresca M, Yahi N, Puigserver A, Fantini J
J Biol Chem 2002 Mar 29;277(13):11292-6.		Medline
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Point mutationE200K (True positive)
Reference #21Corsaro A, Thellung S, Russo C, Villa V, Arena S, D'Adamo MC, Paludi D, Rossi Principe D, Damonte G, Benatti U, Aceto A, Tagliavini F, Schettini G, Florio T
Neurochem Int 2002 Jul;41(1):55-63.		Medline
Text sourceabstract
Point mutationE200K (True positive)
Reference #22Wegner C, Romer A, Schmalzbauer R, Lorenz H, Windl O, Kretzschmar HA
J Gen Virol 2002 May;83(Pt 5):1237-45.		Medline
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Point mutationE200K (True positive)
Reference #23Mitrova E, Belay G
Acta Virol 2002;46(1):31-9.		Medline
Text sourceabstract
Point mutationE200K (True positive)
Reference #24Capellari S, Parchi P, Wolff BD, Campbell J, Atkinson R, Posey DM, Petersen RB, Gambetti P
Neurology 2002 Nov 26;59(10):1628-30.		Medline
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Point mutationE200K (True positive)
Reference #25Mastrangelo P, Serpell L, Dafforn T, Lesk A, Fraser P, Westaway D
FEBS Lett 2002 Dec 4;532(1-2):21-6.		Medline
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Point mutationE200K (True positive)
Cited point mutationE200K,E200
Reference #26Jarius C, Kovacs GG, Belay G, Hainfellner JA, Mitrova E, Budka H
Acta Neuropathol (Berl) 2003 May;105(5):449-54.		Medline
Text sourceabstract
Point mutationE200K (True positive)
Reference #27Atarashi R, Nishida N, Shigematsu K, Goto S, Kondo T, Sakaguchi S, Katamine S
J Biol Chem 2003 Aug 1;278(31):28944-9. Epub 2003 May 19.		Medline
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Point mutationE200K (True positive)
Reference #28Fraser E, McDonagh AM, Head M, Bishop M, Ironside JW, Mann DM
Neuropathol Appl Neurobiol 2003 Oct;29(5):482-95.		Medline
Text sourceabstract
Point mutationE200K (Not yet checked)
Reference #29Harris DA
Br Med Bull 2003;66:71-85.		Medline
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Point mutationE200K (Not yet checked)
Reference #30Gambetti P, Kong Q, Zou W, Parchi P, Chen SG
Br Med Bull 2003;66:213-39.		Medline
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Point mutationE200K (True positive)
Reference #31Tremblay P, Ball HL, Kaneko K, Groth D, Hegde RS, Cohen FE, DeArmond SJ, Prusiner SB, Safar JG
J Virol 2004 Feb;78(4):2088-99.		Medline
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Point mutationE200K (True positive)
Reference #32Apetri AC, Surewicz K, Surewicz WK
J Biol Chem 2004 Apr 23;279(17):18008-14. Epub 2004 Feb 2.		Medline
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Point mutationE200K (True positive)
Reference #33Goldman JS, Miller BL, Safar J, de Tourreil S, Martindale JL, Prusiner SB, Geschwind MD
Arch Neurol 2004 Feb;61(2):213-6.		Medline
Text sourceabstract
Point mutationE200K (Not yet checked)
Reference #34Asante EA, Li YG, Gowland I, Jefferys JG, Collinge J
Neurosci Lett 2004 Apr 22;360(1-2):33-6.		Medline
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Point mutationE200K (Not yet checked)
Reference #35Zanusso G, Farinazzo A, Prelli F, Fiorini M, Gelati M, Ferrari S, Righetti PG, Rizzuto N, Frangione B, Monaco S
J Biol Chem 2004 Sep 10;279(37):38936-42. Epub 2004 Jul 9.		Medline
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Point mutationE200K (Not yet checked)
Reference #36Pocchiari M, Puopolo M, Croes EA, Budka H, Gelpi E, Collins S, Lewis V, Sutcliffe T, Guilivi A, Delasnerie-Laupretre N, Brandel JP, Alperovitch A, Zerr I, Poser S, Kretzschmar HA, Ladogana A, Rietvald I, Mitrova E, Martinez-Martin P, de Pedro-Cuesta J, Glatzel M, Aguzzi A, Cooper S, Mackenzie J, van Duijn CM, Will RG
Brain 2004 Oct;127(Pt 10):2348-59. Epub 2004 Sep 10.		Medline
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Point mutationE200K (Not yet checked)
Reference #37Ladogana A, Puopolo M, Poleggi A, Almonti S, Mellina V, Equestre M, Pocchiari M
Neurology 2005 May 10;64(9):1592-7.		Medline
Text sourceabstract
Point mutationE200K (Not yet checked)
Reference #38Gabizon R, Telling G, Meiner Z, Halimi M, Kahana I, Prusiner SB
Nat Med 1996 Jan;2(1):59-64.		Medline
Text sourceabstract
Point mutationE200K (True positive)
Reference #39Tateishi J, Kitamoto T, Hoque MZ, Furukawa H
Neurology 1996 Feb;46(2):532-7.		Medline
Text sourceabstract
Point mutationE200K (True positive)
Reference #40Petersen RB, Parchi P, Richardson SL, Urig CB, Gambetti P
J Biol Chem 1996 May 24;271(21):12661-8.		Medline
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Point mutationE200K (Not yet checked)
Reference #41Antoine JC, Laplanche JL, Mosnier JF, Beaudry P, Chatelain J, Michel D
Neurology 1996 Apr;46(4):1123-7.		Medline
Text sourceabstract
Point mutationE200K (True positive)
Cited point mutationGlu200Lys
Reference #42Daude N, Lehmann S, Harris DA
J Biol Chem 1997 Apr 25;272(17):11604-12.		Medline
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Point mutationE200K (Not yet checked)
Reference #43Meiner Z, Gabizon R, Prusiner SB
Medicine (Baltimore) 1997 Jul;76(4):227-37.		Medline
Text sourceabstract
Point mutationE200K (True positive)
Reference #44Rosenmann H, Halimi M, Kahana I, Biran I, Gabizon R
Neurology 1997 Sep;49(3):851-6.		Medline
Text sourceabstract
Point mutationE200K (True positive)
Reference #45DeArmond SJ, Sanchez H, Yehiely F, Qiu Y, Ninchak-Casey A, Daggett V, Camerino AP, Cayetano J, Rogers M, Groth D, Torchia M, Tremblay P, Scott MR, Cohen FE, Prusiner SB
Neuron 1997 Dec;19(6):1337-48.		Medline
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Point mutationE200K (Not yet checked)
Reference #46Priola SA, Chesebro B
J Biol Chem 1998 May 8;273(19):11980-5.		Medline
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Point mutationE200K (Not yet checked)
Reference #47Riek R, Wider G, Billeter M, Hornemann S, Glockshuber R, Wuthrich K
Proc Natl Acad Sci U S A 1998 Sep 29;95(20):11667-72.		Medline
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Point mutationE200K (True positive)
Cited point mutationGlu200Lys,Glu-200-Lys
Reference #48Prusiner SB
Proc Natl Acad Sci U S A 1998 Nov 10;95(23):13363-83.		Medline
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Point mutationE200K (Not yet checked)
Reference #49Miyakawa T, Inoue K, Iseki E, Kawanishi C, Sugiyama N, Onishi H, Yamada Y, Suzuki K, Iwabuchi K, Kosaka K
Neurol Res 1998 Dec;20(8):684-8.		Medline
Text sourceabstract
Point mutationE200K (True positive)

Relevant sentences

Reference #25 (Mastrangelo P et al.): E200
  • Properties of E196K , E200K , and E211Q F-CJD mutations 3.4

  • Expressed in transfected rodent cells , F-CJD alleles of Prnp neither engender bona fide protease-resistant PrPSc nor prion infectivity [8 , 9 , 10 and 11 ] and transgenic mice expressing the E200K mutation do not develop spontaneous neuropathology or prion infectivity [11 and 12 ]

  • Materials and methods Experimental structures of recombinant wt PrP , E200K PrP and mouse Dpl were available from the Protein Data Bank (entries 1QLX , 1F07 and 1I17 , respectively) (http: / / www.rcsb.org / pdb )

  • On the other hand , a relationship was noted for five F-CJD mutations (V180I , E196K , E200K , V210I , and E211Q: Table 1 )

  • Of these , V180I , E196K , E200K and E211Q result in amino acid changes that are exactly conserved in human Dpl , while V210I involves an isoleucine conserved in mouse , cow , sheep and rat Dpl proteins ( Fig. 1 )

  • E200 , mutated to lysine in the E200K F-CJD allele , is the N-terminal residue of helix C in both PrP and Dpl , while V210 and E211 , mutated to I and Q respectively in F-CJD , are bracketed on the N-terminal side by an invariant R208 residue and on the C-terminal side by C214

  • The sixth instance comprises E196 , which is mutated to lysine in F-CJD and is positioned on the C-terminal side by the aforementioned E200 residue

  • Failure to define a constant relationship between the nucleotide codons of V180 , E196 , E200 and E211 and their equivalents in the human Dpl gene lead us to consider the properties of the respective proteins

  • Properties of E196K , E200K , and E211Q F-CJD mutations These F-CJD mutants all affect (wt) glutamic acid residues in human PrP , are perfect matches to the analogous human Dpl residues , and result in a change to a basic residue

  • All are closely juxtaposed and face upwards (E200 and E211) or outwards (E196) from the plane of the α ; B-loop-α ; C sub-domain [13 and 31 ]

  • To assess further similarities between Dpl and mutant PrP C the NMR solution structure determined for recombinant human E200K PrP [13 ] (RMSD = 0.4– ; 0.7 Å ; ) was overlaid on the Dpl NMR structure

  • Overlay yielded an RMSD of 1.87 Å ; for the E200K PrP– ; Dpl comparison versus 3.50 Å ; for the wt PrP– ; Dpl comparison , emphasizing the similarity between the E200K PrP and wt Dpl [32 ](bold text in Table 1 )

  • We modeled E200K in the same fashion as an internal control

  • RMSD values of the superimposable Cα ; atoms of the E196K (2.36 Å ; ) , E200K (2.18 Å ; ) and E211Q (2.23 Å ; ) proteins are lower than wt PrP (3.5 Å ; ) , indicating that these structures are more Dpl-like

  • The RMSD value for the modeled E200K– ; Dpl comparison is larger than that for the experimentally determined structure E200K– ; Dpl comparison (2.18 Å ; versus 1.87 Å ; ) , suggesting that these molecular dynamics analyses may underestimate similarities with Dpl

  • 3D models of human PrP , human PrP E200K and mouse Dpl

  • The residues under consideration are Glu196 , Glu200 and Glu211 for human PrP ; Glu196 , Lys200 and Glu211 for human PrP E200K ; and Lys125 , Lys129 and Lys140 for mouse Dpl

  • Considered collectively , averaged RMSD values per atom for V180I , E196K , E200K , V210I and E211Q were 2.24± ; 0.09 Å ; , versus 3.50 and 3.45 Å ; for wt PrP and D178N PrP , respectively

  • The data also showed a tendency for a greater number of superimposed residues and identical residues in the alignment when again considering V180I , E196K , E200K , V210I and E211Q mutant proteins versus wt PrP and D178N PrP (Table 1 )

  • Decreased expression of the wt allele has been implicated in disease onset in E200K carriers , perhaps by reducing a protective effect [43 ] and homozygosity for E200K has been reported to hasten disease onset [44 ]

  • Expressed in transfected rodent cells , F-CJD alleles of Prnp neither engender bona ¢de protease-resistant PrPSc nor prion infectivity [8^11] and transgenic mice expressing the E200K mutation do not develop spontaneous neuropathology or prion infectivity [11 , 12]

  • On the other hand , a relationship was noted for ¢ve F-CJD mutations (V180I , E196K , E200K , V210I , and E211Q: Table 1)

  • Wild type 61 3.50 13 D178N (11) G(S) A , E , G , H , Y , V 178N 61 3.45 13 V180I (4) I (I) A , D , G , L , F 180I 59 2.26 12 E196K (3) K(K) A , D , E , G , Q , V , Stop 196K 71 2.38 15 E200K (63) K(K) A , D , E , G , V , Stop 200K 66 2.18 18 200K NMR structure 68 1.87 15 V210I (5) V(I) n.a

  • Failure to de¢ne a constant relationship between the nucleotide codons of V180 , E196 , E200 and E211 and their equivalents in the human Dpl gene lead us to consider the properties of the respective proteins

  • Properties of E196K , E200K , and E211Q F-CJD mutations These F-CJD mutants all a¡ect (wt) glutamic acid residues in human PrP , are perfect matches to the analogous human Dpl residues , and result in a change to a basic residue

  • All are closely juxtaposed and face upwards (E200 and E211) or outwards (E196) from the plane of the KB-loop-KC sub-domain [13 , 31]

  • To assess further similarities between Dpl and mutant PrPC the NMR solution structure determined for recombinant human E200K PrP [13] (RMSD = 0.4^0.7 Aî ) was overlaid on the Dpl NMR structure

  • Overlay yielded an RMSD of 1.87 Aî for the E200K PrP^Dpl comparison versus 3.50 Aî for the wt PrP^Dpl comparison , emphasizing the similarity between the E200K PrP and wt Dpl [32](bold text in Table 1)

  • RMSD values of the superimposable CK atoms of the E196K (2.36 Aî ) , E200K (2.18 Aî ) and E211Q (2.23 Aî ) proteins are lower than wt PrP (3.5 Aî ) , indicating that these structures are more Dpl-like

  • The RMSD value for the modeled E200K^Dpl comparison is larger than that for the experimentally determined structure E200K^Dpl comparison (2.18 Aî versus 1.87 Aî ) , suggesting that these molecular dynamics analyses may underestimate similarities with Dpl

  • Considered collectively , averaged RMSD values per atom for V180I , E196K , E200K , V210I and E211Q were 2.24 þ 0.09 Aî , versus 3.50 and 3.45 Aî for wt PrP and D178N PrP , respectively

  • Decreased expression of the wt allele has been implicated in disease onset in E200K carriers , perhaps by reducing a protective e¡ect [43] and homozygosity for E200K has been reported to hasten disease onset [44]

Reference #1 (Parchi P et al.): E200K
  • Ghetti Insomnia associated with thalamic involvement in E200K Creutzfeldt-Jakob disease Neurology , February 12 , 2002 ; 58(3): 362 - 367

Reference #2 (Narwa R et al.): E200K
  • E199K is homologous to a human mutation (E200K) linked to CJD (35 , 36) Mutant PrPs Remain Partially Resistant to PIPLC after Solubilization in Nondenaturing Detergents

  • E199K is homologous to a human mutation (E200K) linked to CJD (35 , 36)

Reference #4 (Mallucci GR et al.): E200K
  • Incomplete penetrance was reported with the E200K mutation , although recent evidence suggests that penetrance approaches 100% by age 85 years (Meiner et al. , 1997(image) )

  • In inherited prion disease E200K there appears to be no association between age at onset and genotype at PRNP codon 129

Reference #5 (Rosenmann H et al.): E200K
  • Alert me when: new articles cite this article Download to Citation Manager Neurology 1999 ; 53:1328 © 1999 American Academy of Neurology ------------------------------------------------------------------------ Brief Communications Preliminary evidence for anticipation in genetic E200K Creutzfeldt-Jakob disease H

  • Creutzfeldt-Jakob disease (CJD) linked to the E200K mutation of the prion protein (PrP) gene presents within a wide range of phenotypic heterogeneity , including the age at disease onset

  • Key words: Creutzfeldt-Jakob disease—E200K mutation—Libyan Jewish

  • In this community , the disease was linked with a lod score >4.8 to the E200K in the PrP gene

  • 1 -3 E200K CJD presents with a wide range of age at disease onset , as well as variable disease duration and clinical patterns

  • 4 , 5 We investigated whether anticipation , 6 , 7 an earlier age at onset , or more severe phenotype in successive generations is a feature of familial CJD linked to the E200K mutation , as it is in myotonic dystrophy and Huntington’s disease

  • We recorded the age at disease onset of 95 parent-offspring pairs from 44 E200K CJD-affected pedigrees of Libyan Jewish origin

  • Members of the offspring generation were diagnosed as genetic CJD patients based on clinical manifestations and detection of the E200K mutation in the PrP gene

  • When no medical information was available for either parent , we considered the parent who died younger as the E200K CJD transmitting parent and recorded this parent’s age at death as age at onset of CJD

  • This was also the case when eight older , healthy E200K mutation carriers were added to the offspring generation in the highly reliable group , and their present age was considered as the age at CJD onset

  • The results constitute preliminary evidence that in familial CJD linked to the E200K mutation , heterogeneity of clinical presentation is accompanied by anticipation

  • It will be also interesting to compare our results with data on CJD-affected Libyan Jews living in other countries (France and Italy) , as well as with other carriers of the E200K mutation , such as the ones originating from Slovakia

  • Spudich S , Mastrianni JA , Wrensch M , et al. Complete penetrance of Creutzfeldt-Jakob disease in Libyan Jews carrying the E200K mutation in the prion protein gene

  • Brief Communications Preliminary evidence for anticipation in genetic E200K Creutzfeldt-Jakob disease Article abstract--Creutzfeldt-Jakob disease (CJD) linked to the E200K mutation of the prion protein (PrP) gene presents within a wide range of phenotypic heterogeneity , including the age at disease onset

  • In this community , the disease was linked with a lod score 4.8 to the E200K in the PrP gene.1-3 E200K CJD presents with a wide range of age at disease onset , as well as variable disease duration and clinical patterns.4 , 5 We investigated whether anticipation , 6 , 7 an earlier age at onset , or more severe phenotype in successive generations is a feature of familial CJD linked to the E200K mutation , as it is in myotonic dystrophy and Huntington's disease

  • When no medical information was available for either parent , we considered the parent who died younger as the E200K CJD transmitting parent and recorded this parent's age at death as age at onset of CJD

  • This was also the case when eight older , healthy E200K mutation carriers were added to the offspring generation in the highly reliable group , and their From the Department of Neurology (Dr

  • It will be also interesting to compare our results with data on CJD-affected Libyan Jews living in other countries (France and Italy) , as well as with other carriers of the E200K mutation , such as the ones originating from Slovakia.10

Reference #6 (Zuegg J et al.): E200K
  • The amino acid residues in black boxes are mutation sites known to be associated with inherited forms of PrP diseases in humans [CJD , D178N:129V (3) , V180I (3) , T183A (3) , E200K (3) , R208H (3) , V210I (3) , and M232R (3) ; GSS , P102L (3) , P105L (3) , A117V (3) , Y145Stop (3) , H187R (14) , F198S (3) , D202N (13) , Q212P (13) , and Q217R (3) ; FFI , D178N:129M (3) ; schizophrenia , N171S (12) ] , while in light gray boxes residues involved in some polymorphisms influencing these diseases are shown [M129V (3) , E219K (11) ]

Reference #7 (Laplanche JL et al.): E200K
  • It could also be explained by chance or better diagnosis in the later generations , or by the large stochastic variance of the age of manifestation of disease , as has been described in familial CJD linked to the E200K PRNP gene mutation in Libyan Jews (Goldfarb et al. , 1990(image) )

Reference #8 (Simon ES et al.): E200K
  • We identified 70 Creutzfeldt-Jakob disease patients with the previously described E200K mutation in the prion protein gene

  • The purpose of this study was to define the clinical features of E200K homozygous patients (n = 5) , compared with heterozygotes

Reference #9 (Mitrova E et al.): E200K
  • An increasing number of new CJD cases in hGH recipients in France , providing evidence of unusually long incubation period and an occurrence of genetically controlled (mutation E200K carrier) CJD-risk group in Slovak population induced this second investigation of hGh treated patients

  • The occurrence of codon 200 (E200K) mutation and polymorphism at codon 129 of PrP gene was studied

  • Restriction endonuclease analysis of the PrP gene revealed one patient with E200K mutation , 8 patients homozygous for methionin , 2 patients homozygous for valin and 16 heterozygous patients at codon 129

Reference #10 (Capellari S et al.): E200K
  • 2000 ; 157:613-622.) © 2000 American Society for Investigative Pathology ------------------------------------------------------------------------ Regular Articles Effect of the E200K Mutation on Prion Protein Metabolism Comparative Study of a Cell Model and Human Brain Sabina Capellari , Piero Parchi , Claudio M

  • We used a cell model to study biosynthesis and processing of PrP M carrying the glutamic acid to lysine substitution at residue 200 (E200K) , which is linked to the most common inherited human prion disease

  • Similar changes were found in the PrP isolated from brains of patients affected by the E200K variant of Creutzfeldt-Jakob disease

  • Although the cellular PrP M displayed some characteristics of PrP Sc , the PrP Sc found in the E200K brains was quantitatively and qualitatively different

  • We propose that the E200K mutation cause the same metabolic changes of PrP M in the cell model and in the brain

  • 13 The most common of the human PRNP mutations occurs at codon 200 and results in the substitution of glutamic acid with lysine (E200K) in PrP

  • 14 The E200K mutation is linked to a disease phenotype that resembles that of the typical sporadic CJD , the most common human prion disease

  • 15 Although the presence of the PRNP E200K mutation increases the probability of developing CJD from 1:1 million , the prevalence of the sporadic form , to more than 1:1.1 , the penetrance of the E200K mutation , 15 the carriers of the mutation remain asymptomatic for several decades

  • 15 Therefore , the changes caused by the E200K mutation in the mutant PrP (PrP M) make the conversion of PrP M into PrP Sc almost inevitable , but the disease becomes clinically detectable only after a long incubation time

  • 15 -19 In the present study , we investigated the effects of the PRNP E200K mutation on the metabolism of PrP M in human neuroblastoma cells and we demonstrated several abnormal features of PrP M , such as an abnormal glycosylation , an increased formation of truncated fragments , and a partial insolubility and increased resistance to digestion with proteinase K (PK)

  • Then , we looked for these abnormal features in the PrP extracted from brains of patients affected by the E200K subtype of familial CJD

  • Our results demonstrate that several posttranslational changes are produced by the E200K mutation and are shared by the cell model and the E200K CJD-affected brains

  • However , basic characteristics of the PrP Sc present in the E200K brains are not reproduced by the cell model , suggesting that although the E200K mutation renders PrP M susceptible to conversion into PrP Sc , the conversion requires additional modifications of the protein to occur

  • The following cell lines were used: control / 129M or C , expressing normal PrP , bearing a methionine at codon 129 , or mutant at codon 200 with either methionine (E200K / 129M) or valine (E200K / 129V) at codon 129

  • Moreover , cell lines with PrP mutated at codon 181 or 199 , either combined or not with the E200K mutation (N181Q / 129M ; N181Q / 129M / E200K ; T199A / 129M ; T199A / 129M / E200K) , were constructed

  • Patients and Tissues Four patients carrying the E200K mutation were studied

  • Brain Tissue Gray matter brain samples were obtained from frozen brains of E200K-affected patients and age-related controls

  • The 12-kd fragment became detectable in the intracellular compartment only after a 3-hour chase and was more abundant in the E200K cell preparations than in the controls (Figure 1C)(image)

  • Second , we used N181Q and T199A glycosylation knock-out mutants with or without the E200K substitution , and demonstrated a difference in mobility between the PrP M and PrP C I forms only in the 181-glycan knock-out (N181Q) mutant (Figure 2C)(image)

  • A: Immunoblot of total PrP from a control or E200K-affected brain stained with the 3F4 antibody

  • B: Whole brain lysate from an E200K-affected patient (lane 1) , a control (lane 2) , an E200K brain biopsy of an affected patient (lane 3) , and after digestion of sample 1 with PK (lane 4) ; all samples were probed with the anti-C antibody

  • Type 1 PrP res from sporadic CJD (T1) , E200K CJD , and type 2 PrP res from sporadic CJD (T.2) are shown

  • Note the reduction in the quantity of the E200K U form and the faster migration of all type 2 PrP res forms compared to type 1 PrP res

  • D: PrP from control , E200K-129M and E200K-129V cell lines , before (first three lanes) and after (last three lanes) limited PK digestion , were blotted and immunoreacted with the 3F4 antibody

  • Insolubility and Protease Resistance of PrP M E200K PrP M has been reported to have some of the properties of the PrP Sc , namely insolubility in nonionic detergents as well as partial resistance to PI-PLC and protease treatments

  • PI-PLC was significantly less effective in cleaving the anchor in the E200K than in the control cells (56% ± 6 of PrP M cleaved versus 71% ± 7 of PrP C , P < 0.01 , n = 3) (data not shown)

  • 29 To test whether the increased PrP M resistance to PK digestion was simply the consequence of the increase in the aggregated form , preparations from the E200K and control cells were normalized for the content of the detergent insoluble PrP , and digested with PK (Figure 5D)(image)

  • PrP Properties in E200K CJD Brains To assess the relevance of the alterations observed in the cell model to the corresponding human disease , we compared the cellular PrP M with the total PrP and with PrP Sc extracted from brains of patients affected by the E200K subtype of CJD

  • Although the direct comparison between the two systems is limited by the heterozygosity of the E200K mutation , which results in the presence of both PrP M and PrP C in the brain samples , we observed several similarities (Table 1)(image)

  • Diagram Summarizing the PrP Changes Occurring in the Cells and in the Human Brain The full-length UPrP from the E200K brains appeared as a smear compared to the sharp band of slightly higher mobility present in control brain preparations (Figure 6A)(image)

  • This finding is likely to result from both heterogeneity in gel mobility and reduction in quantity of the U forms in the E200K brain

  • 29 In addition , the 12-kd peptide that was increased in the mutant cells , accounted for ~13% of the total PrP in the E200K CJD brains whereas it was not detected in control brains

  • 33 -35 Although the CJD patients carrying the more common E200K-129M haplotype examined in this study form PrP Sc type 1 , those carrying the rare E200K-129V haplotype form PrP Sc type 2

  • 36 Therefore , we generated a mutant cell line carrying the E200K mutation coupled with valine rather than methionine at codon 129 (E200K-129V)

  • The PrP M expressed by both the E200K cell lines was similarly resistant to PK , and in both cell lines it generated a PK-resistant PrP M fragment that co-migrated at ~20 kd (Figure 6D)(image)

  • Therefore , the E200K cell models do not reproduce the PrP Sc dualism found in the corresponding human diseases (Figure 6C)(image)

  • Discussion (image)Top (image)Abstract (image)Introduction (image)Experimental Procedures (image)Results (image)Discussion (image)References The neuroblastoma cell model carrying the E200K mutation in PRNP demonstrates the presence of several posttranslational changes of PrP M that are related to the mutation

  • As previously observed in cell models carrying this or other PRNP mutations , 16 -18 E200K PrP M also displayed increased aggregation and resistance to PI-PLC and PK treatments

  • 37 , 38 However , this study shows that the E200K mutation does not affect glycosylation efficiency but rather selectively interferes with the modifications of the glycan chain at residue 197 which results in an enhanced gel migration of the highly glycosylated PrP M form

  • The HPrP Sc present in the affected E200K brains and the HPrP M recovered from fibroblasts of affected patients also show an increase in gel mobility that is comparable to what is observed in the cell model

  • In contrast , this may be because of the other changes associated with the E200K mutation , such as the increased aggregation and resistance to PI-PLC and PK treatments , which may all be related to the misfolding and destabilizing effect of the mutation on PrP M

  • The underrepresentation of UPrP M in the cell model is a feature shared by the Q217R and the D178N mutations 23 and is common to the E200K and D178N familial variants of CJD and to Fatal Familial Insomnia

  • 21 , 24 The present study strongly argues that the underrepresentation of the U form in the E200K PrP Sc results from the effect of the E200K mutation on PrP M before , not after , the conversion of PrP M into PrP Sc occurs

  • We confirm that the C-terminal region of E200K PrP M has an increased resistance to PK digestion

  • 33 , 34 Thus , in addition to the most common familial CJD in which the E200K mutation is coupled to the codon 129 expressing methionine and PrP Sc type 1 is present in brain , there also is a E200K-129 valine familial CJD associated with PrP Sc type 2

  • 36 When we modeled these two diseases in cells , the E200K-129 methionine and E200K-129 valine cell lines failed to form the PK-resistant PrP M fragments of 21 kd and 19 kd , respectively , but both lines formed only a PK-resistant PrP M isoform of ~20 kd

  • Therefore , although in the cell model the PrP M reproduces the changes associated with the E200K mutation and makes PrP M susceptible to convert into the PrP Sc form , the cellular PrP M does not undergo this conversion and remains different from PrP Sc

  • 41 -43 Thus , we propose that the E200K mutation (and other PRNP mutations having a similar effect) cause the tertiary structure to extend toward the N-terminal region to include the unstructured 112 to 90 segment

  • In the E200K affected brains , as well as in other prion diseases , this extended C-terminal region is likely to be the site of major conformational changes during the conversion of PrP C to PrP Sc

  • 29 In conclusion , our data show that multiple alterations in PrP M are driven by the E200K mutation

Reference #11 (Stewart RS et al.): E200K
  • It has been speculated that some mutations like E200K indirectly enhance formation of CtmPrP by first causing accumulation of PrP Sc (22 )

Reference #12 (Tagliavini F et al.): E200K
  • CJD E200K illustrates an intermediate state , as the wild-type PrP is insoluble but protease-sensitive (23 )

Reference #13 (Rosenmann H et al.): E200K
  • Creutzfeldt-Jakob disease (CJD) in Libyan Jews , linked to the E200K mutation in PRNP (E200KCJD) , is the most prevalent of the inherited prion diseases

  • As other prion diseases , E200KCJD is characterized by the brain accumulation of PrP(Sc) , a pathologic conformational isoform of a normal glycoprotein denominated PrP(C)

  • To investigate whether the E200K mutation is enough to de novo confer PrP(Sc) properties to mutant PrP , as suggested by experiments in Chinese hamster ovary cells , we examined the biochemical behavior of E200KPrP in brains and fibroblasts from sporadic as well as homozygous and heterozygous E200KCJD patients , asymptomatic transgenic mice carrying the E200K mutation , as well as in normal and scrapie-infected mouse neuroblastoma cells expressing E200KPrP

  • E200KPrP was examined for protease sensitivity , solubility in detergents , releasibility by phosphoinositol phospholypase-C and localization in cholesterol enriched membrane microdomains (rafts)

  • In all tissues except in brains of CJD patients and ScN2a cells , E200KPrP displayed properties similar to those of PrP(C)

  • Our results indicate that the E200K mutation does not automatically convey the properties of PrP(Sc) to new PrP molecules

Reference #14 (Negro A et al.): E200K
  • Bovine homologues of human E200K and D178N (129M) mutations were used as models of pathogenic isoforms

Reference #16 (Ivanova L et al.): E200K
  • Finally , biochemical analyses have suggested that human E200K and D178N PrPs are not transported efficiently to the cell surface (18 , 21 ) , and localization studies using GFP chimeras indicate that the bovine versions of these mutants are present in the ER (22 )

Reference #17 (Daniels M et al.): E200K
  • Human mutations E200K and F198S were found to enhance toxicity of PrP121-231 to PrP-knockout neurones and E200K enhanced toxicity to wild-type neurones

Reference #18 (Lorenz H et al.): E200K
  • In addition , four cellularly well defined PrP mutants (GFP-PrP P101L , GFP-PrP W144 Stop , GFP-PrP D177N , and GFP-PrP E199K as the mouse homologues for human PrP P102L , Y145 Stop , D178N , E200K) were used as controls to evaluate the GFP-PrP model system and to extend the existing knowledge about these mutants (7 , 17 , 19 , 20 )

  • Biochemical as well as cellular data have been described for four of the seven disease-related PrP mutants , i.e. the three full-length PrP mutants PrP P102L , PrP D178N , PrP E200K (7 , 19 ) and the truncated molecule PrP Y145 Stop (20 ) but not for PrP Q160 Stop , PrP T188K , and PrP T188R (human PrPs)

  • GFP-PrP chimera with mouse PrPa Human PrP Phenotype P101L P102L GSS W144Stopb Y145Stop GSS Q159Stop Q160Stop EODc D177N D178N FFI T187K T188K CJD T187R T188R CJDd E199K E200K CJD a Mouse PrP contains methionine at position 128 , which corresponds to codon 129 in human PrP , a polymorphic site encoding either methionine or valine

Reference #19 (Mastrianni JA et al.): E200K
  • Transgenic (Tg) mice expressing a chimeric human-mouse PrP transgene were inoculated with brain extracts from three fCJD(V210I) cases , sporadic CJD (sCJD) , fCJD(E200K) , and fatal familial insomnia (FFI) , to compare prion strain characteristics

  • The pattern of PrP Sc deposition in the brains of Tg mice was similar to that caused by sCJD but different from that associated with fCJD(E200K) or FFI

  • 4 -6 Other mutations such as E200K are genetically linked to a typical Creutzfeldt-Jakob disease (CJD)-like presentation

  • Our findings suggest that fCJD(V210I) shares a clinicopathologic and experimental phenotype with sporadic CJD (sCJD) but not with fCJD(E200K) or FFI(D178N , M129)

  • Incubation periods and regional deposition of PrP Sc in the brains of Tg mice were compared with those of sCJD(M / M129) , fCJD(E200K) , and FFI(D178N , M129) prion diseases , which were previously studied

  • Genetic screening and confirmation by sequence analysis of previously acquired sCJD , fCJD(E200K) , and FFI(D178N) cases were also performed

  • These were compared with the PrP Sc accumulation pattern caused by sCJD(M / M129) , fCJD(E200K) , and FFI(D178N , M129) prions (figure 4 )

  • Differences were more obvious between fCJD(V210I) and fCJD(E200K)

  • 6 These differences in histoblot patterns among the familial prion diseases , along with the atypical pathologic features of fCJD(V210I) , argue that the V210I mutation produces a strain of prions that is similar to those of sCJD but different from that of fCJD(E200K) and FFI

  • Histoblot of brain tissue from Tg(MHu2M)Prnp 0 / 0 mice inoculated with human brain homogenates from cases of familial Creutzfeldt-Jakob disease (fCJD(V210I)) (A , B) , sporadic CJD (sCJD) (C , D) , fCJD(E200K) (E , F) , and fatal familial insomnia (G , H)

  • 29 In contrast , PrP Sc accumulation was widespread throughout the cerebral cortex , basal ganglia , diencephalon , and brainstem with homogenates from fCJD(E200K)

  • Third , the accumulation of PrP Sc caused by fCJD(V210I) prions is different from those caused by fCJD(E200K) and FFI(D178N , M129) prions

  • The observed variability in symptom onset and neuropathologic changes that we noted among the V210I patients compares with that reported with fCJD(E200K)

  • 7 , 30 It is important to note that penetrance of the E200K mutation in fCJD was initially calculated to be 0.56 , 31 but subsequent life table analyses of fCJD(E200K) families showed that the risk of developing disease is nearly complete by the ninth decade of life

  • 32 , 33 Penetrance for carriers of the E200K mutation is as low as 1% at age 40 and close to 100% at age 80 34 and is associated with the relative expression levels of mutant to wild-type PrP C

  • Healthy carriers had lower expression levels of mutated PrP C(E200K) , whereas most of the clinically ill patients had equal levels of expression

Reference #20 (Mahfoud R et al.): E200K
  • The V3-like domain of PrP is a disulfide-linked loop (Cys179-Cys214) that includes the E200K mutation site associated with familial Creutzfeldt-Jakob disease

  • The synthetic peptides P1 (KQHTVTTTTKGENFTETDVKMMER) and P2 (KQHTVTTTTKGENFTKTDVKMMER) respectively derived from the human PrP protein and the E200K mutant were purchased from Euro Sequence Gene service (Evry , France)

  • Increases in the surface pressure induced by the indicated concentrations of peptide P1 (wild-type sequence , squares) or P2 (E200K mutant sequence , circles) added in the aqueous subphase were determined

  • Effect of Mutation E200K in Human PrP for Sphingolipid Recognition-- The V3-like region of human PrP contains a mutation site (E200K) corresponding to the most common familial form of the Creutzfeldt-Jakob disease (1 )

  • Another synthetic peptide similar to P1 but bearing the E200K substitution was therefore synthesized (P2) , and its interaction with sphingolipids was also analyzed using the lipid monolayer assay

  • From a structural point of view , these data are consistent with the high level of structural homology between the wild-type and the E200K mutant of human PrP (27 )

  • The main effects of the E200K mutation are (i) major changes in the distribution of charges on the protein surface and (ii) the loss of a salt-bridge interaction between the side chains of Glu200 and Lys204

  • In any case , the E200K mutation has little (if any) effect on the orientation and accessibility of aromatic residues that are involved in binding to GalCer

  • However , the redistribution of surface charges induced by the E200K mutation may dramatically affect the interaction of PrP with charged lipids such as sphingomyelin

  • These data show that the E200K mutation specifically affected the recognition of sphingomyelin

Reference #21 (Corsaro A et al.): E200K
  • We synthesized the polypeptides 90-231 of both the wild type and the E200K mutant isoforms of PrP

  • The same procedure was also successfully employed to synthesize and purify the E200K mutant PrP fragment.

Reference #22 (Wegner C et al.): E200K
  • In the latter study , the authors found that , under such conditions , the introduction of the human-pathogenic mutations P102L , D178N , T183A and E200K and an insertion of six additional octapeptides in the ORF of Prnp at the respective locations (P101L , D177N , T183A and E199K) rendered the mutated proteins resistant to PK at the above concentration

Reference #23 (Mitrova E et al.): E200K
  • In the Slovak CJD group 95 out of 136 CJD cases (74.2%) carried a CJD-specific mutation in the prion protein gene (PRNP) at codon 200 (mutation E200K)

  • All CJD(E200K) patients carried a heterozygous E200K mutation within the alelle with methionine at codon 129

  • The penetrance of the E200K mutation in 1975-2000 was 59.5%

  • Genetic analysis performed on 278 CJD patient relatives demonstrated the E200K mutation in 97 (34.8%) of healthy relatives tested

  • The E200K mutation carriers were methionine-homozygous in 64% and methionine / valine-heterozygous in 36%

  • Analysis ofthe E200K carriers provided evidence that the methionine homozygosity is a CJD risk factor , more efficient in CJD patients than in asymptomatic relatives

  • Th influence of both the E200K mutation and methionine homozygosity at codon 129 was evident in the duration of the clinical stage of CJD and in the immunoreactivity pattern of PrP resistant to proteases (PrP(res))

  • In the CJD(E200K) methionine-homozygous patients the mean duration ofthe disease was significantly shorter (3.7 + / - 2.0 months) than in the methionine / valine-heterozygous patients (7.84 + / - 7.3 months)

  • Comparison of the PrP(res) positivity in the cerebellum of familial and sporadic CJD using specific polyclonal and monoclonal antibodies (MAbs) to PrP showed less conspicuous immune reaction in CJD(E200K) cases

  • The percentage of professions related to farming was significantly higher in CJD(E200K) (48%) and sporadic CJD (44%) cases as compared to the employed population (9%).

Reference #24 (Capellari S et al.): E200K
  • In both patients the disease duration exceeds that of familial forms of CJD linked to the E200K or V210I mutations that have phenotypes similar to that of the sporadic CJD MM1 subtypes

Reference #25 (Mastrangelo P et al.): E200K
  • Properties of E196K , E200K , and E211Q F-CJD mutations 3.4

  • Expressed in transfected rodent cells , F-CJD alleles of Prnp neither engender bona fide protease-resistant PrPSc nor prion infectivity [8 , 9 , 10 and 11 ] and transgenic mice expressing the E200K mutation do not develop spontaneous neuropathology or prion infectivity [11 and 12 ]

  • Materials and methods Experimental structures of recombinant wt PrP , E200K PrP and mouse Dpl were available from the Protein Data Bank (entries 1QLX , 1F07 and 1I17 , respectively) (http: / / www.rcsb.org / pdb )

  • On the other hand , a relationship was noted for five F-CJD mutations (V180I , E196K , E200K , V210I , and E211Q: Table 1 )

  • Of these , V180I , E196K , E200K and E211Q result in amino acid changes that are exactly conserved in human Dpl , while V210I involves an isoleucine conserved in mouse , cow , sheep and rat Dpl proteins ( Fig. 1 )

  • E200 , mutated to lysine in the E200K F-CJD allele , is the N-terminal residue of helix C in both PrP and Dpl , while V210 and E211 , mutated to I and Q respectively in F-CJD , are bracketed on the N-terminal side by an invariant R208 residue and on the C-terminal side by C214

  • Properties of E196K , E200K , and E211Q F-CJD mutations These F-CJD mutants all affect (wt) glutamic acid residues in human PrP , are perfect matches to the analogous human Dpl residues , and result in a change to a basic residue

  • To assess further similarities between Dpl and mutant PrP C the NMR solution structure determined for recombinant human E200K PrP [13 ] (RMSD = 0.4– ; 0.7 Å ; ) was overlaid on the Dpl NMR structure

  • Overlay yielded an RMSD of 1.87 Å ; for the E200K PrP– ; Dpl comparison versus 3.50 Å ; for the wt PrP– ; Dpl comparison , emphasizing the similarity between the E200K PrP and wt Dpl [32 ](bold text in Table 1 )

  • We modeled E200K in the same fashion as an internal control

  • RMSD values of the superimposable Cα ; atoms of the E196K (2.36 Å ; ) , E200K (2.18 Å ; ) and E211Q (2.23 Å ; ) proteins are lower than wt PrP (3.5 Å ; ) , indicating that these structures are more Dpl-like

  • The RMSD value for the modeled E200K– ; Dpl comparison is larger than that for the experimentally determined structure E200K– ; Dpl comparison (2.18 Å ; versus 1.87 Å ; ) , suggesting that these molecular dynamics analyses may underestimate similarities with Dpl

  • 3D models of human PrP , human PrP E200K and mouse Dpl

  • The residues under consideration are Glu196 , Glu200 and Glu211 for human PrP ; Glu196 , Lys200 and Glu211 for human PrP E200K ; and Lys125 , Lys129 and Lys140 for mouse Dpl

  • Considered collectively , averaged RMSD values per atom for V180I , E196K , E200K , V210I and E211Q were 2.24± ; 0.09 Å ; , versus 3.50 and 3.45 Å ; for wt PrP and D178N PrP , respectively

  • The data also showed a tendency for a greater number of superimposed residues and identical residues in the alignment when again considering V180I , E196K , E200K , V210I and E211Q mutant proteins versus wt PrP and D178N PrP (Table 1 )

  • Decreased expression of the wt allele has been implicated in disease onset in E200K carriers , perhaps by reducing a protective effect [43 ] and homozygosity for E200K has been reported to hasten disease onset [44 ]

  • Expressed in transfected rodent cells , F-CJD alleles of Prnp neither engender bona ¢de protease-resistant PrPSc nor prion infectivity [8^11] and transgenic mice expressing the E200K mutation do not develop spontaneous neuropathology or prion infectivity [11 , 12]

  • On the other hand , a relationship was noted for ¢ve F-CJD mutations (V180I , E196K , E200K , V210I , and E211Q: Table 1)

  • Wild type 61 3.50 13 D178N (11) G(S) A , E , G , H , Y , V 178N 61 3.45 13 V180I (4) I (I) A , D , G , L , F 180I 59 2.26 12 E196K (3) K(K) A , D , E , G , Q , V , Stop 196K 71 2.38 15 E200K (63) K(K) A , D , E , G , V , Stop 200K 66 2.18 18 200K NMR structure 68 1.87 15 V210I (5) V(I) n.a

  • Properties of E196K , E200K , and E211Q F-CJD mutations These F-CJD mutants all a¡ect (wt) glutamic acid residues in human PrP , are perfect matches to the analogous human Dpl residues , and result in a change to a basic residue

  • To assess further similarities between Dpl and mutant PrPC the NMR solution structure determined for recombinant human E200K PrP [13] (RMSD = 0.4^0.7 Aî ) was overlaid on the Dpl NMR structure

  • Overlay yielded an RMSD of 1.87 Aî for the E200K PrP^Dpl comparison versus 3.50 Aî for the wt PrP^Dpl comparison , emphasizing the similarity between the E200K PrP and wt Dpl [32](bold text in Table 1)

  • RMSD values of the superimposable CK atoms of the E196K (2.36 Aî ) , E200K (2.18 Aî ) and E211Q (2.23 Aî ) proteins are lower than wt PrP (3.5 Aî ) , indicating that these structures are more Dpl-like

  • The RMSD value for the modeled E200K^Dpl comparison is larger than that for the experimentally determined structure E200K^Dpl comparison (2.18 Aî versus 1.87 Aî ) , suggesting that these molecular dynamics analyses may underestimate similarities with Dpl

  • Considered collectively , averaged RMSD values per atom for V180I , E196K , E200K , V210I and E211Q were 2.24 þ 0.09 Aî , versus 3.50 and 3.45 Aî for wt PrP and D178N PrP , respectively

  • Decreased expression of the wt allele has been implicated in disease onset in E200K carriers , perhaps by reducing a protective e¡ect [43] and homozygosity for E200K has been reported to hasten disease onset [44]

Reference #26 (Jarius C et al.): E200K
  • We have compared the immunomorphological spectrum of the deposition of the disease-associated prion protein (PrP(Sc)) in the cerebral and cerebellar cortex of 32 Creutzfeldt-Jakob disease (CJD) patients with the PrP gene (PRNP) E200K mutation to 45 sporadic CJD and 14 other genetic prion disease cases

  • While the diffuse / synaptic and patchy / perivacuolar PrP deposits and PrP plaques have a similar distribution and correlation with the genotype at codon 129 as in sporadic CJD , an additional peculiar PrP immunostaining pattern occurs in the cerebellum in 81% E200K mutation brains including 93% of M129M , 71% of M129V , but not in the single V129V case

Reference #27 (Atarashi R et al.): E200K
  • Mo.E199K represents the E200K substitution in human PrP , which is commonly found in patients with familial Creutzfeldt-Jakob disease (21 )

  • The solution structure of recombinant human PrP 90-231 with E200K was reported to be nearly identical to that of wild-type PrP (25 )

Reference #28 (Fraser E et al.): E200K
  • The relationships between the degree of cortical prion protein (PrP) deposition , tissue vacuolation and astrocytosis were studied in the frontal cortex of 27 cases of human spongiform encephalopathy , encompassing 13 cases of sporadic Creutzfeldt-Jakob disease (sCJD) , four cases of familial CJD (fCJD) (one owing to E200K mutation , one owing to 144 bp insertion , one owing to P102L mutation and one owing to A117V mutation) , five cases of iatrogenic CJD (iCJD) owing to growth hormone therapy and five cases of variant CJD (vCJD)

Reference #29 (Harris D et al.): E200K
  • Capellari S , Parchi P , Russo CM et al. Effect of the E200K mutation on prion protein metabolism

Reference #30 (Gambetti P et al.): E200K
  • CJD with the E200K-129M haplotype (CJD E200K-129M) CJDE200K-129M is the most common form of familial CJD

  • Clinical features CJDE200K-129M is similar to sCJDMM1 , the most common subtype of sCJD6 , 7 , 58

  • CJDE200K-129M patients also show signs of motor and sensory peripheral neuropathy rarely found in sCJD patients

  • The CSF 14-3-3 protein is elevated in almost all the CJDE200K cases65 , 66

  • Different PrP patterns in the cerebellum have been reported for CJDE200K-129M subjects with Met or Val at codon 129 on the normal allele , with a synaptic pattern for 129MM subjects and granules and plaque-like structures for 129MV subjects69

  • The PrPSc in CJDE200K-129M is of type 1 and is characterised by the under-representation of the unglycosylated form30 , 70 , similar to that observed in FFI (see below) and in vCJD30 , 32

  • Brain homogenates from CJDE200K-129M patients have been used successfully to infect apes71 and humanised transgenic mice72 CJD with the E200K-129V haplotype (CJD E200K-129V) The E200K-129V haplotype has been reported52 in five subjects from apparently unrelated families , and all have type 2 PrPSc

  • In contrast to those of E200K-129M , the phenotypes of the E200K-129V haplotype are similar to those of sCJDVV27 , presenting as ataxia at onset followed by myoclonus and PSW complexes on EEG examination

  • Lane 1 , sCJD 129MM , PrPSc type 1 ; lane 2 , sCJD 129VV , PrPSc type 2 ; lane 3 , fCJD E200K-129M , PrPSc type 1 ; lane 4 , fCJD E200K-129V , PrPSc type 2 ; lane 5: fCJD 144bp-Insert-129M , PrPSc type 1 ; lane 6 , fCJD V210I-129M , PrPSc type 1

  • (image)Fatal familial insomnia (image)Acknowledgements (image)References The D178N-129M haplotype associated with FFI is among the most prevalent familial CJD after CJDE200K

  • Spudich S , Mastrianni JA , Wrensch M et al. Complete penetrance of Creutzfeldt-Jakob disease in Libyan Jews carrying the E200K mutation in the prion protein gene

  • Simon ES , Kahana E , Chapman J et al. Creutzfeldt-Jakob disease profile in patients homozygous for the PRNP E200K mutation

  • Creutzfeldt-Jakob disease with E200K mutation in Slovakia: characterization and development

Reference #31 (Tremblay P et al.): E200K
  • The E200K and A117V mutations produced neurologic diseases , but brains from Tg mice carrying these mutations failed to transmit disease on passage in wt or isogenic hosts (24 ; P

Reference #32 (Apetri AC et al.): E200K
  • All variants containing mutations linked to familial prion diseases (P102L , D178N with 129M and 129V polymorphism , V180I , F198S , E200K , R208H , V210I , and Q217R) were constructed on the background of W99F / Y218W huPrP-(90-231) (21 ) by site-directed mutagenesis using appropriate primers and the QuikChange kit (Stratagene)

  • These data show that whereas some of the disease-associated mutations produce a pronounced decrease in the global stability of Y218W / W99F huPrP-(90-231) , the effect of others (e.g. P102L and E200K) is essentially negligible

  • Two notable exceptions are the E200K and P102L variants , in which cases mutations have very little effect on either the global protein stability (as measured by (image)) or the stability of the folding intermediate

  • Data of Table II indicate that at least for two PrP variants , P102L and E200K , the population of an intermediate is similar to that for the wild-type prion protein , even though the intermediate state is always much more populated than the fully unfolded state

  • For the E200K variant , these factors may include an alteration of surface electrostatic potential , as observed in a recent NMR structural study (54 )

Reference #33 (Goldman JS et al.): E200K
  • Although there was no family history of neurological disease , an E200K mutation was found

Reference #34 (Asante EA et al.): E200K
  • We investigated whether one of the commonest of these mutations , E200K , results in a functionally inactive prion protein by expressing human PrP 200K in transgenic mice homozygous for murine PrP null alleles

  • The mutation studied here , the substitution of lysine for glutamate at codon 200 (E200K) , is one of the most prevalent , being responsible for the high incidence of CJD amongst Libyan Jews and in areas of Slovakia and Chile and is recognised in many countries [8 ]

  • While the exact mechanism of the conversion of PrPC to PrPSc is not understood , it is thought that the E200K and other pathogenic mutations in PRNP could predispose the mutant PrPC to spontaneous conversion to the disease isoform [7 ]

  • We have investigated the functional properties of the E200K mutant prion protein in animal models , using transgenic mice homozygous for human PrP E200K mutation on the polymorphic PRNP residue 129-methionine background

  • Inherited E200K mutation has been reported on both the codon 129 valine or methionine allele of PRNP

  • These were then bred together to obtain the transgenic line designated Tg(HuPrP E200K , 129MM)23+ / + , homozygous for the human codon 200K mutant transgene on the codon 129 methionine allele (Tg23+ / +)

  • The expression level of E200K PrPC in Tg23+ / + was estimated at ~3 times normal levels of wild type PrPC in pooled human brain (not shown)

  • Therefore the mutant human PrP transgene , which produces E200K PrP C at ~3 times normal levels in human brain , restored the null phenotype to wild type status

  • The two PrP knockout lines (filled symbols) have smaller AHPs than the two with PrP , whether wild type or mutant E200K

  • These results clearly demonstrate rescue of the electrophysiological PrP null phenotype by the expression of the E200K mutant human PrP C

  • Another group reported that biochemical properties such as protease sensitivity , solubility in detergents and releasibility by phosphoinositol phospholypase-C measured in fibroblast and brain tissues were similar in asymptomatic E200K transgenics , wild type mice and normal mouse neuroblastoma cells expressing E200KPrP C [15 ]

  • PrP null mice are resistant to pathogenic prions [3 ] ; our preliminary prion transmission data show that homozygous E200K transgenic mice (Tg23+ / +) , lacking the endogenous mouse PrP gene , have acquired susceptibility to prions and propagate both sporadic and inherited CJD E200K prions to a similar extent (Asante et al. , unpublished data)

  • The physiological , biochemical or pathological data from the present and other studies indicate that the mutant E200K PrP C rescues the PrP null phenotype

  • Taken together they argue that , in inherited E200K prion disease , the mutant protein , although predisposing to spontaneous neurodegeneration during adult life , has the functional properties of the normal cellular prion protein

Reference #35 (Zanusso G et al.): E200K
  • Previous studies have disclosed that an internal PrP fragment of 7-8 kDa detected in patients with P102L Gerstmann-Sträussler-Scheinker disease (7 , 25 ) and a C-terminal fragment associated with familial Creutzfeldt-Jakob disease due to E200K mutation (26 ) are toxic to neurons in combination with or in the absence of PrP expression (27 , 28 )

Reference #36 (Pocchiari M et al.): E200K
  • The Bonferroni correction for multiple testing was adopted within the five subgroups of gTSE (E200K and V210I gCJD , GSS , FFI and insert mutations) and the two subgroups of iCJD patients

  • An analysis was only performed for the two most frequent PRNP mutations (i.e. E200K and V210I)

  • Median clinical duration (Table 5 ) for E200Kand V210I patients was 4 months

  • In the univariate Cox analysis , survival of both E200K and V210I patients was shorter in males than in females

  • Though both mutations co-segregate with methionine at codon 129 , methionine homozygosity was associated with a shorter survival in E200K patients , but a long survival in V210I patients (Table 5 , Fig. 3 )

  • In E200K patients , the only significant predictor of survival remained the polymorphism at codon 129

  • View this table: [in this window] [in a new window]   Table 4 Clinical duration of disease in genetic CJD patients carrying different point mutations of the PRNP gene View this table: [in this window] [in a new window]   Table 5 Survival times for genetic CJD (E200K and V210I) View larger version (29K): [in this window] [in a new window]   Fig. 3 Influence of codon 129 genotype on Kaplan-Meier survival curves in (A) E200K CJD , (B) V210I CJD , (C) FFI , (D) human growth hormone-related CJD

Reference #37 (Ladogana A et al.): E200K
  • The most frequent mutation was the V210I (n = 54) , and the second most common the E200K (n = 42)

Reference #38 (Gabizon R et al.): E200K
  • We studied prion proteins (PrP) in skin and brains of Libyan Jews carrying the E200K mutation who died of familial Creutzfeldt-Jakob disease (CJD)

  • Using monospecific antisera , we found that wtPrP was insoluble in the brains of three patients who were heterozygous for the E200K mutation , whereas mutant PrP was both insoluble and protease-resistant

Reference #39 (Tateishi J et al.): E200K
  • Sporadic Creutzfeldt-Jakob disease (CJD) with 129M / M , and iatrogenic and familial CJD with E200K and M232R , showed similar clinicopathologic features , a synaptic type deposition of PrPCJD , and high transmission frequencies to mice

Reference #40 (Petersen RB et al.): E200K
  • Petersen Effect of the E200K Mutation on Prion Protein Metabolism : Comparative Study of a Cell Model and Human Brain Am

Reference #42 (Daude N et al.): E200K
  • Gabizon et al. (41 ) have detected a form of wild-type PrP that is detergent-insoluble but protease-sensitive in the brains of heterozygous patients carrying an E200K mutation , although it was not possible in their experiments to determine by metabolic labeling whether this was a true intermediate that could be converted into a protease-resistant form

Reference #43 (Meiner Z et al.): E200K
  • Initially , this high incidence was attributed to infection via consumption of sheep brains or eyeballs , but a mutation at codon 200 in PRNP resulting in the substitution of lysine (K) for glutamate (E) , designated E200K , was identified in this population

  • The onset of fCJD (E200K) is age dependent and shows nearly complete penetrance by age 85 years

  • fCJD (E200K) has been transmitted to primates and transgenic mice , highlighting the need to address ethical and public health issues surrounding the possibility of human to human transmission.

Reference #44 (Rosenmann H et al.): E200K
  • Creutzfeldt-Jakob disease (CJD) linked to the E200K mutation of the prion protein (PrP) gene presents with a wide range of age at disease onset

  • We measured wt and mutant PrP protein and mRNA in Epstein-Barr virus (EBV)-transformed B cells of either E200K CJD patients or healthy E200K carriers

  • Our results suggests that while in most healthy carriers the expression of wt PrP was higher than that of E200K PrP , most of the E200K CJD patients express equal levels of both PrP proteins

Reference #45 (DeArmond SJ et al.): E200K
  • As controls , cryostat sections were prepared for histoblots from Tg mice expressing (E) wild-type MHu2M PrPC , (F) MHu2M PrPC(D178N) , and (G) MHu2M PrPC(E200K)

  • To address this issue , we examined the effects of other mutations known to modify the extent of glycosylation and to cause compared the patterns of PrPC immunostaining in the brains of Tg mice expressing wild-type chimeric PrP with mutant PrP carrying either the D178N or E200K mutation: the distribution of mutant PrPs was indistinguishable from that of wild-type PrPC (Figure 2 E2G)

Reference #46 (Priola SA et al.): E200K
  • Petersen Effect of the E200K Mutation on Prion Protein Metabolism : Comparative Study of a Cell Model and Human Brain Am

Reference #48 (Prusiner S et al.): E200K
  • Recent studies on the transmission of mutant prions from FFI and fCJD(E200K) to Tg(MHu2M) mice , which results in the formation of two different PrP Sc molecules (27 ) , has forced a corollary to the ubiquitous virus postulate

  • Even more difficult to imagine is how one ubiquitous virus might acquire different mutant PrP Sc molecules corresponding to FFI or fCJD(E200K) and then induce different MHu2M PrP Sc conformers upon transmission to Tg mice

  • Additionally , brain extracts from patients with some other inherited prion diseases , fCJD(E200K) or FFI , transmit disease to Tg(MHu2M) mice (27 )

  • In FFI , the protease-resistant fragment of PrP Sc after deglycosylation has a mass of 19 kDa , whereas in fCJD(E200K) and most sporadic prion diseases it is 21 kDa (Table 6 ) (273 , 274 )

  • Distinct prion strains generated in humans with inherited prion diseases and transmitted to Tg mice Extracts from the brains of FFI patients transmitted disease to mice expressing a chimeric MHu2M PrP gene about 200 days after inoculation and induced formation of the 19-kDa PrP Sc , whereas fCJD(E200K) and sCJD produced the 21-kDa PrP Sc in mice expressing the same transgene (27 )

  • On second passage , Tg(MHu2M) mice inoculated with FFI prions showed an incubation time of approx 130 days and a 19-kDa PrP Sc , whereas those inoculated with fCJD(E200K) prions exhibited an incubation time of approx 170 days and a 21-kDa PrP Sc (28 )

  • In contrast , fCJD(E200K) prions inoculated into Tg(MHu2M) mice produced widespread deposition of PrP Sc throughout the cortical mantle and many of the deep structures of the CNS (Fig. 9 B) as is seen in fCJD(E200K) of humans

  • (B) The Tg mouse was inoculated with extract from a patient with fCJD(E200K)

  • Sonnichsen Solution Structure of the E200K Variant of Human Prion Protein

Reference #49 (Miyakawa T et al.): E200K
  • Five of the 7 cases , including the 3 familial cases , had the E200K mutation in the gene encoding prion protein (PRNP)

  • It is suggested that there is a small cluster of CJD patients with a founder effect of the E200K mutation in the Fuji area , because the incidence of CJD with the E200K mutation appears to be much higher in this area than other areas in Japan

  • The disease penetrance of the 5 cases with the E200K mutation seems to be low , and they may have an age-related incidence in the Fuji area

Reference #15 (Thompson AJ et al.): Glu-200-Lys
  • Interestingly , Glu-200-Lys is a pathogenic mutation responsible for a familial form of TSE

  • The importance of Glu-200 for small alpha , Greek-helical formation in this region indicates that a Glu-200-Lys mutation could promote PrPSc formation through influencing local helical propensity

Reference #47 (Riek R et al.): Glu-200-Lys
  • The mutations Glu-200-Lys and Arg-208-His (Fig. 1 d) are located on the protein surface , so that even the change in overall charge of the protein should not have a major impact on the global structure

Reference #3 (Cardone F et al.): Glu200Lys
  • We analysed PrP27-30 glycotypes in a large number of TSE-affected patients: 50 sporadic CJD (sCJD) , 1 iatrogenic CJD , 1 Gerstmann-Straussler-Scheinker syndrome (GSS) with the Pro102Leu mutation of PrP , 3 familial CJD (fCJD) with the Glu200Lys mutation and , for the first time , 7 fCJD with the Val210ll3e mutation

  • In Glu200Lys fCJD and GSS patients , we found that PrP27-30 has the same mobility of type 1 but different glycosylation ratios (type 1B)

Reference #41 (Antoine JC et al.): Glu200Lys
  • We performed a study of the distribution of PrP27-30 , the proteinase-K-resistant form of prion protein , in the central and peripheral nervous system of a patient with a Glu200Lys mutation of the prion protein gene , cerebellar ataxia , subcortical dementia , rigidity , and demyelinating peripheral neuropathy

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F.Horn (priondbcmbi.ru.nl), 22-Aug-2005