NR AKMF
AU Schätzl,H.M.; Wopfner,F.; Gilch,S.; von Brunn,A.; Jäger,G.
TI Is codon 129 of prion protein polymorphic in human beings but not in animals?
QU Lancet 1997 May 31; 349(9065): 1603-4
KI Lancet. 1997 Aug 30;350(9078):668. PMID: 9288076
PT letter
VT
In human beings, there is a polymorphism at aminoacid position 129 of the prion protein which influences susceptibility to prion infection. In European populations, the usual distribution pattern is about 50% heterozygosity for methionine/valine (Met/Val), 40% homozygosity for methionine (Met/Met), and 10% for valine (Val/Val). Methionine homozygosity predisposes to sporadic Creutzfeldt Jakob disease (CJD) as well as acquired CJD.[1] In patients with new variant CJD (nvCJD) Met/Met has been invariably found.[2] Structural models ascribe importance to position 129 in stabilising the conformation of PrP by interaction with other aminoacid residues. Conformational change from alpha-helical to ß-sheet structure is thought to be a primary event in prion diseases. The figure shows the location of the alpha-helical regions revealed by computer-assisted structure prediction and of structural regions determined by a nuclear magnetic resonance-based model of murine PrP(121-231).[3]
We investigated whether codon 129 had a similar allelic distribution in other mammals. Our sequence analysis of about 150 samples representing more than 50 mammalian species has shown a remarkable uniformity of homozygosity for methionine at this position.[4] This finding applies also for non-human mammalian PrPs analysed by other groups. Why the aminoacid 129 is polymorphic in humans but not in animals is unclear. Aminoacid polymorphisms at other positions in murine and sheep PrP have been shown to affect susceptibility to prion disease.
Wapiti deer GQGG-THSQWNKPSKPKTNMKHVAGAAAAGAVVGGLGGYL
Dybowski deer - M
Sheep - SMR.S
Cattle - ..GMSHS
Mouse G..NLMMW. . . . . . . . . . . . . . . . S
Human GMMISHM.E.S
4-Helix - alpha alpha alpha alpha
NMR-PrP (121-231) ßßßß alpha ßßßß
Wapiti deer LGSAMSRPLIHFGNDYEDRYYRENMYRYPNQVYYRPVDQYN
Dybowski deer
Sheep
Cattle
Mouse
Human
4-Helix
NMR-PrP (121-231)
Predicted aminoacid sequences of Wapiti and Dybowski deer were compared to PrPs of sheep, cattle, mouse, and human beings. Dots indicate identical aminoacids. Location of postulated
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Here we report the first mammalian PrP with an aminoacid other than methionine at the position 129. The PrP gene of the Wapiti deer (Cervus elaphus canadensis) encodes leucine at both alleles (figure). DNA extracted from peripheral lymphocytes of three independent samples (kindly provided by Dr Gaukler, Zoological Gardens at Nürnberg, Germany) were PCR amplified with degenerate primers and the PCR fragments were sequenced directly. Analysis of another deer species (Cervus nippon dybowskii, Dybowski deer) found methionine at this position. Interestingly, a prion disorder named chronic wasting disease has been found in elks and deers in Montana, USA.5 Whether this disorder is acquired by infection or has a sporadic or genetic origin is unknown.
In view of the current epidemic of bovine spongiform encephalopathy (BSE) further sequence analysis of cattle and other ungulates would be advisable as genotype variability of the PrP gene might influence susceptibility to infection with BSE-derived prions.
Literature
1 Palmer MS, Dryden AJ, Hughes JT, et al. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 1991; 352: 340-42.
2 Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996; 347: 921-25.
3 Riek R, Hornemann S, Wider G, Billeter M, Glockshuber R, Wüthrich K. NMR structure of the mouse protein domain PrP (121-231). Nature 1996; 382: 180-82.
4 Schätzl HM, Da Costa M, Taylor L, Cohen FE, Prusiner SB. Prion protein gene variation among primates. J Mol Biol 1995; 245: 362-74.
5 Williams ES, Young S. Chronic wasting disease of captive mule deer: a spongiform encephalopathy. J Wildl Dis 1980; 16: 89-98.
MH Alleles; Amino Acid Sequence; Animal; Codon/*genetics; Deer; Genetic Predisposition to Disease; Human; Molecular Sequence Data; Polymerase Chain Reaction; Polymorphism (Genetics); Prion Diseases/genetics; Prions/*genetics
AD Hermann M Schätzl, Franziska Wopfner, Sabine Gilch, Albrecht von Brunn, Gundula Jäger, Genecenter, Max von Pettenkofer-Institut für Virology, University of Munich, D-81377 Munich, Germany (H M Schätzl)
SP englisch
PO England
OR Prion-Krankheiten 7