A Polish pedigree with Alzheimer's disease determined by a novel mutation in exon 12 of the presenilin 1 gene: clinical and molecular characterization.

The presenilin 1 (PS-1) gene, recently identified on chromosome 14q24.3, is a major gene involved into the autosomal dominant forms of early onset Alzheimer's disease (EOAD). Mutations of the PS-1 gene are responsible for the majority of familial EOAD. We found a novel mutation in a Polish family with EOAD from the Poznań region. The mutation at codon 424 in exon 12 of the PS-1 gene leads to an amino acid substitution Leu-Arg in a transmembrane domain VIII of the presenilin 1 molecule. The change is predicted to have a drastic effect on the protein function because it is associated with a very early age of onset (a range of 30-35 years) and a quick progression (about a 4-5 years duration) of the disease.