2 NOVEL PRESENILIN-1 MUTATIONS (SER169LEU AND PRO436GLN) ASSOCIATED WITH VERY EARLY-ONSET ALZHEIMERS-DISEASE

MUTATIONS in the presenilin-1 (PS-1) gene account for the majority of early onset autosomal-dominant familial Alzheimer's disease (FAD) case s. We identified three missense mutations in the coding sequence of th e PS-1 gene in three early onset (EO), FAD pedigrees. Alzheimer's dise ase was confirmed in one pedigree by autopsy. Mutation analysis of PCR products amplified from genomic DNA templates of affected individuals showed two novel mutations resulting in Ser169Leu and Pro436Gln and o ne known mutation resulting in Glu318Gly. The two new mutations are lo cated within predicted transmembrane domains three (TM-3) and seven (T M-7), and are associated with a very early age of onset which is consi stent with a marked loss of function of the protein. The age of onset in the pedigree with Glu318Gly mutation was similar to that reported p reviously in a separate pedigree with this mutation. (C) 1998 Lippinco tt Williams & Wilkins.