ABSTRACT
The presenilins constitute an evolutionarily conserved family of ubiquitiously expressed, multiple transmembrane domain proteins. To date, the genes for two mammalian presenilin proteins, termed presenilin 1 (PS1) and presenilin 2 (PS2) have been identified and localized to human chromosome 14 (Sherrington et al., 1995) and chromosome 1 (Levy-Lehad et al., 1995; Rogeav et al., 1995; Li et al., 1995) respectively. Interestingly, although the proteins encoded by the two genes are highly homologus and have an overall amino acid identity of 63% (Levy-Lehad et al., 1995, Rogeav et al., 1995), intensive mutation and epidemiological analyses has revealed some interesting differences between the two proteins. The number of identified mutations in PS1 is far greater than those in PS2. More than 50 individual point mutations in PS1 have been identified and found to be responsible for the majority of early-onset familial Alzheimer’s disease. All but one of these are point mutations that result in single amino acid changes. In contrast, only two mutations in PS2, both of which are point mutations, have been identified and linked to kindred-specific forms of the disease. The first PS2 mutation to be identified results in an asparagine to isoleucine change at amino acid 141 (N141I) and is responsible for the disease in a large Volga-German kindred (Levy-Lehad et al., 1995). The second PS2 mutation causes a methionine to valine change at amino acid 239 (M239V) and was identified in an Italian pedigree (Rogeav et al., 1995). Whether the preponderance of PS1 verses PS2 mutations is due to the differing genomic environment of the two genes or to factors related to differing biological function of the two molecules remains unclear. Mutation analysis of the two proteins has also lead to the identification of a phenotypic difference. Generally, mutations in PS1 result in a relatively early and constant age-of-onset while mutations in PS2 lead to a somewhat later and more variable age-ofonset (Bird et al., 1996). The recent identification of a PS1 asparagine to isoleucine disease-associated mutation at amino acid 135, a position and alteration that corresponds to the PS2 Volga German mutation, and the finding that the affected members of this pedigree have a relatively constant age-ofonset suggests that the observed variations in age-of-onset are dependent on the molecule itself as opposed to the specific position or nature of the amino acid alteration (Crook et al., 1997).
