Genetic basis of Creutzfeldt-Jakob disease in the United Kingdom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene |
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| Authors: | 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 |
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| Institution: | (1) Centre for Genome Research, University of Edinburgh, King’s Buildings, West Mains Road, Edinburgh, UK, GB;(2) National CJD Surveillance Unit, Western General Hospital, Edinburgh, UK, GB;(3) Roslin Institute (Edinburgh), Roslin, Midlothian EH25 9PS, UK, GB;(4) Prion Disease Group, St. Mary’s Hospital, London W2 1PG, UK Fax: +44-171-7067094, GB |
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| 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.
Received: 18 December 1995 / Revised: 19 January 1996 |
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