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1.
Hum Mutat ; 31(7): E1551-63, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20583301

ABSTRACT

Mutation of the human prion protein gene (PRNP) open reading frame (ORF) accounts for almost all reported familial concurrence of prion disease. The more common mutations globally: octapeptide repeat insertions, P102L, D178N, E200K, and V210I have occurred in large multigenerational pedigrees and display autosomal dominant inheritance, however, many rare genetic changes have been reported that are of uncertain pathogenicity. Based on 19 years of PRNP sequencing at the MRC Prion Unit, London, and analysis of 3664 samples from patients referred with suspected prion disease and healthy populations, we present novel allele combinations, healthy control population data, results of screening the PRNP ORF in DNA from the entire referral series and the CEPH human genome diversity cell line panel. Of the 10 alleles detected in patients for which detailed cases histories are presented, 4 are unreported (G54S, D167N, V209M, Q212PP), two changes are thought to be pathogenic but have not been described in our regions (P105L from the UK, G114V from India and Turkey), and the remainder reported in healthy control populations or in trans to known pathogenic mutations suggesting non- or low pathogenicity (G54S, 1-OPRI, G142S, N171S, V209M, E219K). New genotype-phenotype correlations and population frequencies presented will help the diagnosis and genetic counselling of those with suspected inherited prion disease.


Subject(s)
Alleles , Mutation, Missense , Prion Diseases/genetics , Prions/genetics , DNA Mutational Analysis/methods , Gene Frequency , Genetic Association Studies , Genotype , Humans , London , Prion Diseases/diagnosis
3.
Hum Mol Genet ; 13(12): 1219-24, 2004 Jun 15.
Article in English | MEDLINE | ID: mdl-15115757

ABSTRACT

Alzheimer's disease (AD) is the commonest neurodegenerative disease worldwide. Rare familial cases may be caused by mutations in one of three genes-amyloid precursor protein, presenilin-1 and presenilin-2; however, the molecular basis of >99% of AD cases is unknown. Somatic mutation has been considered to be a mechanism that may account for a proportion of sporadic cases of AD, but to date there has been no evidence for this. We now report a sporadic early-onset patient with AD, and show that this individual is a somatic mosaic for a mutation in the presenilin-1 gene, suggesting a novel molecular mechanism for AD. Quantification of the mosaicism demonstrated the degree of mosaicism at 8% in peripheral lymphocytes and 14% in cerebral cortex in the index patient; a clear gene dosage effect on age of presentation and clinical phenotypic presentation is demonstrated. This finding has important implications for the aetiology of sporadic AD, and for other apparently sporadic neurodegenerative diseases such as Parkinson's disease, motor neuron disease and Creutzfeldt-Jakob disease.


Subject(s)
Alzheimer Disease/genetics , Germ-Line Mutation/genetics , Membrane Proteins/genetics , Mosaicism , Adult , Age of Onset , Base Sequence , Female , Humans , Male , Middle Aged , Pedigree , Presenilin-1
4.
Science ; 300(5619): 640-3, 2003 Apr 25.
Article in English | MEDLINE | ID: mdl-12690204

ABSTRACT

Kuru is an acquired prion disease largely restricted to the Fore linguistic group of the Papua New Guinea Highlands, which was transmitted during endocannibalistic feasts. Heterozygosity for a common polymorphism in the human prion protein gene (PRNP) confers relative resistance to prion diseases. Elderly survivors of the kuru epidemic, who had multiple exposures at mortuary feasts, are, in marked contrast to younger unexposed Fore, predominantly PRNP 129 heterozygotes. Kuru imposed strong balancing selection on the Fore, essentially eliminating PRNP 129 homozygotes. Worldwide PRNP haplotype diversity and coding allele frequencies suggest that strong balancing selection at this locus occurred during the evolution of modern humans.


Subject(s)
Disease Outbreaks/history , Ethnicity/genetics , Kuru/history , Polymorphism, Genetic , PrPC Proteins/genetics , Selection, Genetic , Adult , Animals , Cannibalism , Child , Codon , Creutzfeldt-Jakob Syndrome/genetics , Female , Gene Frequency , Haplotypes , Heterozygote , History, 19th Century , History, 20th Century , History, Ancient , Homozygote , Humans , Immunity, Innate , Kuru/epidemiology , Kuru/genetics , Kuru/transmission , Linkage Disequilibrium , Male , Methionine/genetics , Middle Aged , Mutation , Papua New Guinea/epidemiology , Valine/genetics
5.
Neurogenetics ; 4(2): 77-81, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12481985

ABSTRACT

Prion diseases are fatal neurodegenerative disorders of humans and animals, which include bovine spongiform encephalopathy (BSE) and its human form, variant Creutzfeldt-Jakob disease (vCJD). They are characterized by a prolonged incubation period, which is known to be influenced by polymorphisms in the prion protein gene. Previous studies of inbred mice have demonstrated that additional genetic loci also contribute to the observed variation in incubation period. However, a substantial transmission barrier between cow and mouse complicates studies using BSE. As a result, primary transmissions display large variations in incubation period and not all animals develop clinical signs of disease. To identify quantitative trait loci for BSE without the presence of a transmission barrier, we analysed 124 animals from an F2 intercross between CAST/Ei and NZW/OlaHsd mice and challenged them intracerebrally with a strain of BSE that was passaged twice through C57BL/6OlaHsd mice. Interval mapping identified two highly significant linked regions on chromosomes 2 and 11 with peak lod scores of 6.34 and 4.77, respectively. Composite interval mapping suggests that chromosome 2 includes three linked quantitative trait loci. Loci in the same position on chromosomes 2 and 11 were also identified in a previous study using the same mouse cross but infected with Chandler/RML scrapie prions. If these are the same loci, it suggests that these loci may be influencing incubation time independently of prion strain. This provides hope that it may be possible to identify human quantitative trait loci for prion incubation time using mouse models that may allow identification of at-risk individuals and the discovery of novel therapeutic targets.


Subject(s)
Encephalopathy, Bovine Spongiform/genetics , Encephalopathy, Bovine Spongiform/transmission , Genetic Linkage , Animals , Cattle , Chromosomes, Mammalian , Female , Male , Mice , Mice, Inbred C57BL , Prions/genetics , Quantitative Trait Loci , Species Specificity
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