A Novel Mutation in the Predicted TMIII Domain of the PSEN2 Gene in an Italian Pedigree with Atypical Alzheimer's Disease

Abstract . Alzheimer’s disease (AD) is characterized by accumulation of toxic amyloid- β (A β ) in the brain, with neuronal death,and an associated increased A β 42 / 40 ratio. Several mutations in presenilin 1 ( PSEN1 ), presenilin 2 ( PSEN2 ), and amyloid- β precursorproteinareinvolvedintheetiologyoffamilialAD(FAD);thesemutationsaltertheA β 42 / 40 ratioandpromote apoptosis.We describe an Italian pedigree linked to a novel mutation (S175C) at the third transmembrane domain of PSEN2. Clinicalphenotype in these individuals is characterized by fast cognitive decline with progressive memory impairment, early involvementof executive functions, behavioral disturbances, and extrapyramidal signs.Keywords: Atypical dementia, behavioral disturbances, genetics, mutation, presenilins INTRODUCTION Mutations in presenilin 2 gene ( PSEN2 ) on chro-mosome 1 are a cause of autosomal dominant famil-ial Alzheimer’s disease (FAD) [1,2]. Presenilin 2 isan integral protein with nine transmembrane domainsand large, hydrophilic, cytoplasmic loops that under-go regulated endoproteolytic cleavage to produce N-and C-terminal fragments [3,4]. PSEN2 is a subunit of