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Human Genetics

, Volume 98, Issue 3, pp 259–264 | Cite as

Genetic basis of Creutzfeldt-Jakob disease in the United Kingdom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene

  • O. Windl
  • Maureen Dempster
  • J. Peter Estibeiro
  • Richard Lathe
  • Rajith de Silva
  • Thomas Esmonde
  • Robert Will
  • Anthea Springbett
  • Tracy A. Campbell
  • Katie C. L. Sidle
  • Mark S. Palmer
  • J. Collinge
Original investigation

Abstract

Creutzfeldt-Jakob disease (CJD) is a transmissible neurodegenerative disorder characterized by the accumulation of aggregates of a cellular protein, PrP, in the brain. In both human and animals, genetic alterations to the gene encoding PrP (PRNP in human) modulate susceptiblity to CJD. The recent epidemic of bovine spongiform encephalopathy in the UK has raised the possibility of transmission from animal produce to humans. To provide a baseline against which to assess possible risk factors, we have determined the frequencies of predisposing mutations and allelic variants in PRNP and their relative contributions to disease. Systematic PRNP genotype analysis was performed on suspected CJD cases referred to the National Surveillance Unit in the UK over the period 1990–1993. Inspection of 120 candidate cases revealed 67 patients with definite and probable CJD, based on clinical and neuropathological criteria. No PRNP mutations were detected in any of the remaining 53 patients assessed as “non-CJD”. A disease-associated mutation in the PRNP gene was identified in nine (13.4%) definite and probable cases of CJD, a reliable estimate of the incidence of PRNP-related inherited CJD based on a prospective epidemiological series. Within the group of sporadic CJD patients (lacking PRNP mutations), we confirmed that the genotype distribution with respect to the common methionine/valine (Met/Val) polymorphism at codon 129 within PRNP was significantly different from the normal Caucasian population. The incidence of Met homozygosity at this site was more than doubled and correlated with increased susceptibility to the development of sporadic CJD. Unlike other recent studies, Val homozygosity was also confirmed to be a significant risk factor in sporadic CJD, with the relative risks for the three genotypes Met/Met:Val/Val:Met/Val being 11:4:1.

Keywords

Bovine Spongiform Encephalopathy Candidate Case PRNP Gene Surveillance Unit PRNP Genotype 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • O. Windl
    • 1
  • Maureen Dempster
    • 1
  • J. Peter Estibeiro
    • 1
  • Richard Lathe
    • 1
  • Rajith de Silva
    • 2
  • Thomas Esmonde
    • 2
  • Robert Will
    • 2
  • Anthea Springbett
    • 3
  • Tracy A. Campbell
    • 4
  • Katie C. L. Sidle
    • 4
  • Mark S. Palmer
    • 4
  • J. Collinge
    • 4
  1. 1.Centre for Genome Research, University of Edinburgh, King’s Buildings, West Mains Road, Edinburgh, UKGB
  2. 2.National CJD Surveillance Unit, Western General Hospital, Edinburgh, UKGB
  3. 3.Roslin Institute (Edinburgh), Roslin, Midlothian EH25 9PS, UKGB
  4. 4.Prion Disease Group, St. Mary’s Hospital, London W2 1PG, UK Fax: +44-171-7067094GB

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