title: The Distribution of Prion Protein Allotypes Differs Between Sporadic and Iatrogenic Creutzfeldt-Jakob Disease Patients.
abstract: Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent of the human prion diseases, which are fatal and transmissible neurodegenerative diseases caused by the infectious prion protein (PrP(Sc)). The origin of sCJD is unknown, although the initiating event is thought to be the stochastic misfolding of endogenous prion protein (PrP(C)) into infectious PrP(Sc). By contrast, human growth hormone-associated cases of iatrogenic CJD (iCJD) in the United Kingdom (UK) are associated with exposure to an exogenous source of PrP(Sc). In both forms of CJD, heterozygosity at residue 129 for methionine (M) or valine (V) in the prion protein gene may affect disease phenotype, onset and progression. However, the relative contribution of each PrP(C) allotype to PrP(Sc) in heterozygous cases of CJD is unknown. Using mass spectrometry, we determined that the relative abundance of PrP(Sc) with M or V at residue 129 in brain specimens from MV cases of sCJD was highly variable. This result is consistent with PrP(C) containing an M or V at residue 129 having a similar propensity to misfold into PrP(Sc) thus causing sCJD. By contrast, PrP(Sc) with V at residue 129 predominated in the majority of the UK human growth hormone associated iCJD cases, consistent with exposure to infectious PrP(Sc) containing V at residue 129. In both types of CJD, the PrP(Sc) allotype ratio had no correlation with CJD type, age at clinical onset, or disease duration. Therefore, factors other than PrP(Sc) allotype abundance must influence the clinical progression and phenotype of heterozygous cases of CJD.
authors: Rocky Mountain Laboratories, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Hamilton, Montana, United States of America.
authors: Roger A
authors: RA
authors: Moore
authors: National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, School of Clinical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors: Mark W
authors: MW
authors: Head
authors: National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, School of Clinical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors: James W
authors: JW
authors: Ironside
authors: National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, School of Clinical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors: Diane L
authors: DL
authors: Ritchie
authors: Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.
authors: Gianluigi
authors: G
authors: Zanusso
authors: Young Pyo
authors: YP
authors: Choi
authors: Department of Neural Development and Disease, Korea Brain Research Institute, Daegu, Republic of Korea.
authors: Young
authors: Y
authors: Pyo Choi
authors: Rocky Mountain Laboratories, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Hamilton, Montana, United States of America.
authors: Suzette A
authors: SA
authors: Priola
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007049:Iatrogenic Disease; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D018621:PrPC Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018620:PrPSc Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins; D014633:Valine / Q000235:genetics
chemical_list: D018621:PrPC Proteins; D018620:PrPSc Proteins; D011994:Recombinant Proteins; D008715:Methionine; D014633:Valine