17 research outputs found
Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample
We obtained conclusive linkage of Alzheimer disease (AD) with a candidate region of 19.7 cM at 7q36 in an extended multiplex family, family 1270, ascertained in a population-based study of early-onset AD in the northern Netherlands. Single-nucleotide polymorphism and haplotype association analyses of a Dutch patient-control sample further supported the linkage at 7q36. In addition, we identified a shared haplotype at 7q36 between family 1270 and three of six multiplex AD-affected families from the same geographical region, which is indicative of a founder effect and defines a priority region of 9.3 cM. Mutation analysis of coding exons of 29 candidate genes identified one linked synonymous mutation, g.38030G-->C in exon 10, that affected codon 626 of the PAX transactivation domain interacting protein gene (PAXIP1). It remains to be determined whether PAXIP1 has a functional role in the expression of AD in family 1270 or whether another mutation at this locus explains the observed linkage and sharing. Together, our linkage data from the informative family 1270 and the association data in the population-based early-onset AD patient-control sample strongly support the identification of a novel AD locus at 7q36 and re-emphasize the genetic heterogeneity of AD
In vitro analysis of Alzheimer's disease-related presenilin 1 and 2 mutations: effect on beta-amyloid processing
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Systematic analysis of the effect of novel Alzheimer disease PS1/2 mutations on A beta secretion
Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease
Nicastrin significantly modifies risk for familial early-onset Alzheimer's disease in a Dutch population based sample
Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease
Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment
Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable
Mutations in the presenilin 1 ( PSEN1 ) gene have been implicated in
18-50% of autosomal dominant cases with early-onset Alzheimer's disease
(EOAD). Also, PSEN1 has been suggested as a potential risk gene in
late-onset AD cases. We recently showed genetic association in a
population-based study of EOAD, pointing to the 5' regulatory region of
PSEN1. In this study we systematically screened 3.5 kb of the PSEN1
upstream region and found four novel polymorphisms. Genetic analysis
confirmed association of two polymorphisms with increased risk for EOAD.
In addition, we detected two different mutations in EOAD cases at-280
and-2818 relative to the transcription initiation site in exon 1A of
PSEN1. Analysis of the mutant and wild-type-280 variants using luciferase
reporter gene expression in transiently transfected neuroblastoma cells
showed a 30% decrease in transcriptional activity for the mutant-280G
PSEN1 promoter variant compared with the wild-type variant-280C. Our data
suggest that the increased risk for EOAD associated with PSEN1 may result
from genetic variations in the regulatory region leading to altered
expression levels of the PSEN1 protein
Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment
Since the first report showing that Alzheimer disease (AD) might be caused by mutations in the amyloid precursor protein gene (APP), 20 different missense mutations have been reported. The majority of early-onset AD mutations alter processing of APP increasing relative levels of A beta 42 peptide, either by increasing A beta 42 or decreasing A beta 40 peptide levels or both. In a diagnostic setting using direct sequence analysis, we identified in one patient with familial early-onset AD a novel mutation in APP (c.2172G > C), predicting a K724N substitution in the intracytosolic fragment. The mutation is located downstream of the epsilon-cleavage site of APP and is the furthermost C-terminal mutation reported to date. In vitro expression of APP K724N cDNA showed an increase in A beta 42 and a decrease in A beta 40 levels resulting in a near three-fold increase of the A beta 42/A beta 40 ratio. Further, in vivo amyloid positron emission tomography (PET) imaging revealed significantly increased cortical amyloid deposits, supporting that in human this novel APP mutation is likely causing disease.status: publishe