Presenilin 1 Met146Leu variant due to an A&T transversion in an early‐onset familial Alzheimer's disease pedigree from Argentina

Abstract

Most of the cases of early‐onset familial Alzheimer's disease (FAD) are related to missense mutations in the presenilin 1 (PS‐1) gene on chromosome 14. Although PS‐1 mutations are distributed throughout the entire open reading frame, most mutations are found in transmembrane region II and hydrophilic loop VI encoded by exons 5 and 8, respectively. These two groups of substitutions are associated with an age of onset of 40–43 years for exon 5 and 45–55 years for exon 8, respectively. We have previously described a South American pedigree from Argentina with early‐onset FAD (mean age of onset 38.9 ± 3.9 years) with no mutations in exons 16 and 17 of the β‐protein precursor gene (βPP 770 transcript). Here we report the identification of an A±T transversion at the first position of codon 146 of PS‐1 in these patients. This missense mutation results in a Met ± Leu substitution, as reported for the Italian pedigrees Tor 1.1 and FAD4. The significant differences in ages of onset and death among members of generations II—III and IV suggest that other genetic and/or environmental factors may influence disease phenotype in this pedigree.