Two homologous genes associated with early onset familial Alzheimer's disease

We have isolated IWo homologous genes whichbear missense mutatlons in affected members of pedigrees with autosornal dominant early onset Alzheimer disease. The first. prescnilin 1 (PS1) was cloned from chromosome 14 by positional cloning of the AD3 trail. This gene is predicted 10 encode a 467 residue polypeptide bearing at le:t.~t 9 hydrophobic domains and 2 acidic hydrophillic loops. The second. prcsenilin2 (PS2). was isolatetl on the busts of its sequence homology to PS1. and bears a sirnllar suueiure, but differs signific:lntly from PSI in the amino acid sequence of the N-tcrmtnal and intemal acidic hydrophillicdomains. Missense andsplicingmutants preserving the reading (> 20 known mutants in PSI and 2 known muiants in PS2) occur in conserved residues and arc associated with fully penetrant very early onset AD (onset30-55 yrs) inPSI. and with highlypenetrant earlyonset AD (onset 50-70 years) in PS2. Both genes arc widely expressed, but PS2 is expressed at higherlevels in pancreas. cardiacandskeletalmuscle. Both genes have numerous consensussequences for phosphorytatlon by PKC and MAP kinase. but it is currently unknown if thf'.e sites arc actually phosphorylated, Preliminary Irnmunocytochemleal studies using antibodies raised against the non-conserved domains of these proteins suggest that both proteins are predominantly cytoplasmic.