Human Molecular Genetics, Vol 7, 43-51, Copyright © 1998 by Oxford University Press
M Cruts, CM van Duijn, H Backhovens, M Van den Broeck, A Wehnert, S Serneels, R Sherrington, M Hutton, J Hardy, PH St George-Hyslop, A Hofman and C Van Broeckhoven
Two closely related genes, the presenilins ( PS ), located at chromosomes
14q24.3 and 1q42.1, have been identified for autosomal dominant Alzheimer
disease (AD) with onset age below 65 years (presenile AD). We performed a
systematic mutation analysis of all coding and 5'-non-coding exons of PS -1
and PS -2 in a population-based epidemiological series of 101 unrelated
familial and sporadic presenile AD cases. The familial cases included 10
patients of autosomal dominant AD families sampled for linkage analysis
studies. In all patients mutations in the amyloid precursor protein gene (
APP ) had previously been excluded. Four different PS -1 missense mutations
were identified in six familial cases, two of which where autosomal
dominant cases. Three mutations resulted in onset ages above 55 years, with
one segregating in an autosomal dominant family with mean onset age 64
years (range 50-78 years). One PS -2 mutation was identified in a sporadic
case with onset age 62 years. Our mutation data provided estimates for PS
-1 and PS -2 mutation frequencies in presenile AD of 6 and 1% respectively.
When family history was accounted for mutation frequencies for PS -1 were
9% in familial cases and 18% in autosomal dominant cases. Further,
polymorphisms were detected in the promoter and the 5'-non-coding region of
PS -1 and in intronic and exonic sequences of PS -2 that will be useful in
genetic association studies.
ARTICLES
Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease
Laboratory of Neurogenetics, Flanders Interuniversity Institute for Biotechnology (VIB), Born-Bunge Foundation (BBS), University of Antwerp (UIA), Department of Biochemistry, Antwerpen, Belgium.
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