Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant

Abstract

Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 were sought by direct nucleotide sequence analysis of the open reading frame of 60 pedigrees with familial Alzheimer's disease (FAD). In the majority of these pedigrees, PS-1 and beta-amyloid precursor protein (beta APP) gene mutations had been excluded. While no additional PS-2 pathogenic mutations were detected, four silent nucleotide substitutions and alternative splicing of nucleotides 1338-1340 (Glu325) were observed. Analysis of additional members of a pedigree known to segregate a Met239Val mutation in PS-2 revealed that the age of onset of symptoms is highly variable (range 45-88 years). This variability is not attributable to differences in ApoE genotypes. These results suggest (i) that, in contrast to mutations in PS-1, mutations in PS-2 are a relatively rare cause of FAD; (ii) that other genetic or environmental factor modify the AD phenotype associated with PS-2 mutations; and (iii) that still other FAD susceptibility genes remain to be identified.

Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease

“…However, the two groups have very similar neuropathological features. EOFAD is caused by autosomal dominant inheritance of mutations in the amyloid precursor protein (APP) or presenilin genes [9][10][11][12][13][14] in 50% of families, whereas the defective gene(s) in the remainder have yet to be identified. Although EOFAD cases only represent about 5% of all AD patients, studying the EOFAD defective genes has provided considerable insight into AD molecular pathology.…”

Ethnic Differences in Early Onset Alzheimer’s Disease

“…Early-onset familial AD, which typically develops before the age of 65 years and accounts for only a small portion (<1%) of AD cases, is primarily caused by overproduction of Aβ owing to mutations in either the APP gene or genes encoding presenilin 1 (PSEN1) or presenilin 2 (PSEN2), essential components of the γ-secretase complexes responsible for cleavage and release of Aβ [23,35,36]. No relationship between ethnicities and these gene mutations has been observed.…”

Role of Central Insulin-Like Growth Factor-1 Receptor Signalling in Ageing and Endocrine Regulation

“…The A 42:A 40 ratio is a diagnostic tool for APP processing and development of AD (Haass and Selkoe 2007). In addition to age-associated A 42 accumulation, mutations in presenilin 1, presenilin 2 and the APP gene lead to familiar early-onset AD (Tabaton and Tamagno 2007;Sherrington et al 1996;Tanzi et al 1992;Schellenberg et al 1992;Van Broeckhoven et al 1992;St GeorgeHyslop et al 1992;Rogaev et al 1995). The toxic effect of A is not fully understood yet, but might be induced via generation of ion channels, membrane disruption, oxidative stress, induction of apoptosis and inflammation (Hardy and Selkoe 2002;Nakagawa et al 2000;Soto 2003;Roberson and Mucke 2006).…”