NR AMQK
AU Windl,O.; Dempster,M.; Estibeiro,J.P.; Lathe,R.; de Silva,R.N.; Esmonde,T.F.G.; Will,R.; Springbett,A.; Campbell,T.A.; Sidle,K.C.L.; Palmer,M.S.; Collinge,J.
TI Genetic basis of Creutzfeldt-Jakob disease in the United Kingdom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene.
QU Human Genetics 1996 Sep; 98(3): 259-64
PT journal article
AB 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 susceptibility to CJD. The recent epidemic of bovine spongi-form 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.
IN Bei 120 in den Jahren 1990-1993 an das nationale britische CJD-Überwachungsinstitut überwiesenen Patienten mit Verdacht auf Creutzfeldt-Jakob-Krankheit wurden systematische Prionprotein-Genotypanalysen durchgeführt. Bei 67 Patienten wurde die Creutzfeldt-Jakob-Krankheit anhand der klinischen und neuropathologischen Kriterien eindeutig oder als wahrscheinlich diagnostiziert. Bei keinem der 53 unbestätigten Fälle, jedoch bei 9 (13,4%) der 67 bestätigten Fälle wurde eine Mutation in einem Prionproteingen entdeckt. Bei den sicheren oder wahrscheinlichen Creutzfeldt-Jakob-Patienten ohne eine Mutation waren Methionin/ Methionin-Homozygote, aber auch Valin/Valin-Homozygote stark überrepräsentiert. Die relativen Risiken, in die Gruppe der sicheren oder wahrscheinlichen Creutzfeldt-Jakob-Patienten zu kommen, waren für die drei Genotypen Met/Met : Val/Val : Met/Val 11:4:1.
ZR 26
MH Alleles; Base Sequence; Creutzfeldt-Jakob Syndrome/*genetics; DNA Primers; Genetic Predisposition to Disease; Great Britain; Homozygote; Human; Molecular Sequence Data; *Mutation; Prions/*genetics; Support, Non-U.S. Gov't; *Variation (Genetics)
AD Centre for Genome Research, University of Edinburgh, UK
SP englisch
PO Deutschland
OR Prion-Krankheiten 8