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

Abstract

Several lines of evidence suggest a shared genetic susceptibility to Down syndrome (DS) and Alzheimer disease (AD). Rare forms of autosomal-dominant AD 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, kinetochores, and centrosomes, suggesting a function in chromosome segregation. A genetic association between a polymorphism in intron 8 of the PS-1 gene and AD has been described in some series, and an increased risk of AD has been reported in mothers of DS probands. We therefore studied 168 probands with free trisomy 21 of known parental and meiotic origin and their parents from a population-based material, by analyzing the intron 8 polymorphism in the 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) epsilon4 allele (68.0%) was higher than in mothers without epsilon4 (52.2%, P < 0.01). We hypothesize that the PS-1 intronic polymorphism might be involved in chromosomal nondisjunction through an influence on the expression level of PS-1 or due to linkage disequilibrium with biologically relevant polymorphisms in or outside the PS-1 gene.

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

“…For example, as mentioned in the introduction, significant numbers of trisomy 21 and other aneuploid cells have been found in both sporadic and familial AD patients, including individuals carrying a mutation in PS-1 or PS-2 [9,26,31,49,50]. Similarly, two polymorphisms in PS-1, one in the coding sequence and one in the promoter have been found to be associated with both an increased risk of AD and an increased incidence of Down syndrome offspring due to chromosome missegregation during meiosis [24,29]. The finding of endogenous presenilin proteins in structures related to mitosis-centrosomes, kinetochores, and the nuclear envelope -also suggests that PS-1 and 2 play a role in the cell cycle and chromosome segregation [13,18,22].…”

Alzheimer Aβ Peptide Induces Chromosome Mis-Segregation and Aneuploidy, Including Trisomy 21: Requirement for Tau and APP

“…Indeed, a polymorphism in the PS-1 gene is associated with both an increased risk of developing AD and of having a Down syndrome child (Wragg et al , 1996; Higuchi et al , 1996; Petersen et al , 2000; Lucarelli et al , 2004). Furthermore, immunocytochemical and FRET results have shown that endogenous PS-1 and APP and some of their interacting proteins reside in cell structures involved in mitosis, such as the nuclear membrane, centrosomes, or kinetochores (Zimmermann et al , 1988; Li et al , 1997; Honda et al , 2000; Johnsingh et al , 2000; Kimura et al , 2001; Tezapsidis et al , 2003; Zitnik et al , 2006; Nizzari et al , 2007) and become hyperphosphorylated during mitosis (Pope et al , 1994; Suzuki et al , 1994; Preuss et al , 1995).…”

Familial Down syndrome: evidence supporting cytoplasmic inheritance

“…Among the known predisposing factors, advanced maternal age is by far the strongest [1] and, independently of maternal age, genetic mapping shows that certain types of cross‐over at maternal meiosis I confer a substantial susceptibility to non‐disjunction [2]. Parental DNA studies have reported an altered distribution of polymorphisms in the genes for apolipoprotein E, presenilin‐1 and those involved in folate metabolism, but the effects are not great and the results inconsistent between studies [3–6]. Numerous hypotheses have been suggested to explain the underlying mechanism, in particular the maternal factors, in the aetiology of DS, but it remains an enigma [7].…”