PRESENILIN-1 MET146LEU VARIANT DUE TO AN A-]T TRANSVERSION IN AN EARLY-ONSET FAMILIAL ALZHEIMERS-DISEASE PEDIGREE FROM ARGENTINA

Most of the cases of early-onset familial Alzheimer's disease (FAD) ar e related to missense mutations in the presenilin 1 (PS-1) gene on chr omosome 14, Although PS-1 mutations are distributed throughout the ent ire open reading frame, most mutations are found in transmembrane regi on 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 wi th early-onset FAD (mean age of onset 38.9 +/- 3.9 years) with no muta tions in exons 16 and 17 of the beta-protein precursor gene (beta PP77 0 transcript). Here we report the identification of an A-->T transvers ion at the first position of codon 146 of PS-1 in these patients. This missense mutation results in a Met-->Leu substitution, as reported fo r the Italian pedigrees Tor1.1 and FAD4. The significant differences i n ages of onset and death among members of generations II-III and IV s uggest that other genetic and/or environmental factors may influence d isease phenotype in this pedigree.