MOLECULAR-GENETIC ANALYSIS OF FAMILIAL EARLY-ONSET ALZHEIMERS-DISEASELINKED TO CHROMOSOME 14Q24.3

Genetic linkage studies have indicated that chromosome 14q24.3 harbour s a major locus for early-onset (onset age <65 years) Alzheimer's dise ase (AD3). Positional cloning efforts have identified a novel gene S18 2 or presenilin 1 as the AD3 gene, We have mapped S182 in the AD3 cand idate region between D14S277 and D14S284 defined by genetic linkage st udies in the two chromosome 14 linked, early-onset AD families AD/A an d AD/B, We have shown that S182 is expressed in lymphoblasts and have determined the complete cDNA in both brain and lymphoblasts by RT-PCR sequencing, S182 is alternatively spliced in both brain and lymphoblas ts within a putative phosphorylation site located 5' in the coding reg ion. We identified two novel mutations, Ile143Thr and Gly384Ala locate d in, respectively, the second transmembrane domain and in the sixth h ydrophilic loop of the putative transmembrane structure of S182. As fa milies AD/A and AD/B have a very similar AD phenotype our observation of two mutations in functionally different domains suggest that onset age and severity of AD may not be very helpful predictors of the locat ion of putative S182 mutations.