Association between presenilin-1 polymorphism and maternal meiosis II errors in Down syndrome

Several lines of evidence suggest a shared genetic susceptibility to Down s yndrome (DS) and Alzheimer disease (AD), Rare forms of autosomal-dominant A D are caused by mutations in the APP and presenilin genes (PS-1 and PS-2), The presenilin proteins have been localized to the nuclear membrane, kineto chores, and centrosomes, suggesting a function in chromosome segregation. A genetic association between a polymorphism in intron 8 of the PS-1 gene an d AD has been described in some series, and an increased risk of AD has bee n reported in mothers of DS probands, We therefore studied 168 probands wit h free trisomy 21 of known parental and meiotic origin and their parents fr om a population-based material, by analyzing the intron 8 polymorphism in t he PS-1 gene. An increased frequency of allele 1 in mothers with a meiosis II error (70.8%) was found compared with mothers with a meiosis I error (52 .7%, P < 0.01), with an excess of the 11 genotype in the meiosis II mothers . The frequency of allele 1 in mothers carrying apolipoprotein E (APOE) eps ilon 4 allele (68.0%) was higher than in mothers without epsilon 4 (52.2%, P < 0.01), We hypothesize that the PS-1 intronic polymorphism might be invo lved in chromosomal nondisjunction through an influence on the expression l evel of PS-1 or due to linkage disequilibrium with biologically relevant po lymorphisms in or outside the PS-1 gene. (C) 2000 Wiley-Liss, Inc.