Genetic Association of a Cathepsin D Polymorphism and Sporadic Creutzfeldt-Jakob Disease

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Abstract

Background: Cathepsin D is the most abundant lysosomal and endosomal aspartyl protease; it shows beta and gamma secretase activity in vitro by cleaving the amyloid precursor protein into amyloid beta protein. In recent studies, cathepsin D was co-localized with PrP<sup>Sc</sup>, the disease-associated form of the prion disease, and abnormal expression of cathepsin D correlated with tissue damage in brains of sporadic Creutzfeldt-Jakob disease (CJD). Objective: To investigate whether a polymorphism at position 224, C224T, on exon 2 of the cathepsin D gene ( CTSD) is associated with sporadic CJD in the Korean population. Methods: We compared the genotype and allele frequencies at this polymorphism site in 172 sporadic CJD patients with those in 197 healthy Koreans. Results and Conclusion: Our study does not show a significant difference in genotype (p = 0.901) and allele (p = 0.509) frequencies of CTSD C224T between sporadic CJD patients and normal controls. This was the first genetic association study of CTSD in a sporadic CJD population.

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Prion disease genetics.

Simon Mead (2006)

Prion diseases have stimulated intense scientific scrutiny since it was proposed that the infectious agent was devoid of nucleic acid. Despite this finding, genetics has played a key role in understanding the pathobiology and clinical aspects of prion disease through the effects of a series of polymorphisms and mutations in the prion protein gene (PRNP). The advent of variant Creutzfeldt-Jakob disease has confirmed one of the most powerful human genetic susceptibility factors, as all tested patients have an identical genotype at polymorphic codon 129 of PRNP. This review will also consider the accrued reports of inherited prion disease and attempt a genotype-phenotype correlation. The prospects for detection of novel genetic susceptibility factors using mouse models and human genetic association studies will be explored.

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Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease.

M Bodemer, J Laplanche, J Sá … (2000)

To improve diagnostic criteria for sporadic Creutzfeldt-Jakob disease (CJD). Pooled data on initial and final diagnostic classification of suspected CJD patients were accumulated, including results of investigations derived from a coordinated multinational study of CJD. Prospective analysis for a comparison of clinical and neuropathologic diagnoses and evaluation of the sensitivity and specificity of EEG and 14-3-3 CSF immunoassay were conducted. Data on 1,003 patients with suspected CJD were collected using a standard questionnaire. After follow-up was carried out, complete clinical data and neuropathologic diagnoses were available in 805 cases. In these patients, the sensitivity of the detection of periodic sharp wave complexes in the EEG was 66%, with a specificity of 74%. The detection of 14-3-3 proteins in the CSF correlated with the clinical diagnosis in 94% (sensitivity). The specificity (84%) was higher than that of EEG. A combination of both investigations further increased the sensitivity but decreased the specificity. Incorporation of CSF 14-3-3 analysis in the diagnostic criteria for CJD significantly increases the sensitivity of case definition. Amended diagnostic criteria for CJD are proposed.

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Genetic risk factors for variant Creutzfeldt–Jakob disease: a genome-wide association study

Simon Mead, Mark Poulter, James Uphill … (2009)

Summary Background Human and animal prion diseases are under genetic control, but apart from PRNP (the gene that encodes the prion protein), we understand little about human susceptibility to bovine spongiform encephalopathy (BSE) prions, the causal agent of variant Creutzfeldt–Jakob disease (vCJD). Methods We did a genome-wide association study of the risk of vCJD and tested for replication of our findings in samples from many categories of human prion disease (929 samples) and control samples from the UK and Papua New Guinea (4254 samples), including controls in the UK who were genotyped by the Wellcome Trust Case Control Consortium. We also did follow-up analyses of the genetic control of the clinical phenotype of prion disease and analysed candidate gene expression in a mouse cellular model of prion infection. Findings The PRNP locus was strongly associated with risk across several markers and all categories of prion disease (best single SNP [single nucleotide polymorphism] association in vCJD p=2·5×10−17; best haplotypic association in vCJD p=1×10−24). Although the main contribution to disease risk was conferred by PRNP polymorphic codon 129, another nearby SNP conferred increased risk of vCJD. In addition to PRNP, one technically validated SNP association upstream of RARB (the gene that encodes retinoic acid receptor beta) had nominal genome-wide significance (p=1·9×10−7). A similar association was found in a small sample of patients with iatrogenic CJD (p=0·030) but not in patients with sporadic CJD (sCJD) or kuru. In cultured cells, retinoic acid regulates the expression of the prion protein. We found an association with acquired prion disease, including vCJD (p=5·6×10−5), kuru incubation time (p=0·017), and resistance to kuru (p=2·5×10−4), in a region upstream of STMN2 (the gene that encodes SCG10). The risk genotype was not associated with sCJD but conferred an earlier age of onset. Furthermore, expression of Stmn2 was reduced 30-fold post-infection in a mouse cellular model of prion disease. Interpretation The polymorphic codon 129 of PRNP was the main genetic risk factor for vCJD; however, additional candidate loci have been identified, which justifies functional analyses of these biological pathways in prion disease. Funding The UK Medical Research Council.

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Author and article information

Journal

Journal ID (publisher-id): DEM

Journal ID (nlm-ta): Dement Geriatr Cogn Disord

Journal ID (doi): 10.1159/issn.1420-8008

Title: Dementia and Geriatric Cognitive Disorders

Publisher: S. Karger AG

ISSN (Print): 1420-8008

ISSN (Electronic): 1421-9824

Publication date Subscription-year: 2009

Publication date (Print): November 2009

Publication date (Electronic): 13 October 2009

Volume: 28

Issue: 4

Pages: 302-306

Affiliations

^aIlsong Institute of Life Science, Hallym University, Anyang, and ^bSamkwang Medical Laboratories, Seoul, South Korea; ^cNew York State Institute for Basic Research in Developmental Disabilities, New York, N.Y., USA

Article

Publisher ID: 246343 Other ID: Dement Geriatr Cogn Disord 2009;28:302–306

DOI: 10.1159/000246343

PubMed ID: 19828951

SO-VID: 4dfd5942-45ff-46ca-92c4-c83a6513cbce

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date accepted : 08 December 2009

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Tables: 2, References: 38, Pages: 5

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Genetic Association of a Cathepsin D Polymorphism and Sporadic Creutzfeldt-Jakob Disease

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Most cited references 24

Prion disease genetics.

Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease.

Genetic risk factors for variant Creutzfeldt–Jakob disease: a genome-wide association study

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