title: Presenilin-1 mutation E318G and familial Alzheimer's disease in the Italian population.
abstract: Presenilin-1 (PSEN-1) is a component of the gamma-secretase complex involved in beta-amyloid precursor protein (betaAPP) processing. To date about 140 pathogenic mutations in the PSEN-1 gene have been identified and their main biochemical effect is to increase the production of the fibrillogenic peptide Abeta(1-42). An exception is the PSEN-1 [E318G] mutation that does not alter Abeta(1-42) generation and is generally considered a non-pathogenic polymorphism. Nevertheless, this mutation was reported to be a genetic risk factor for familial Alzheimer's disease (FAD) in the Australian population. To independently confirm this indication, we performed a case-control association study in the Italian population. We found a significant association (p<0.05, Fisher's exact test) between the presence of PSEN-1 [E318G] and FAD. In addition, on measuring the Abeta(1-42) and Abeta(1-40) concentrations in fibroblast-conditioned media cultured from PSEN-1 [E318G] carriers and PSEN-1 [wild type] controls we noted a significant decrease (p<0.05, Mann-Whitney test) in the Abeta(1-42)/Abeta(1-40) ratio in PSEN-1 [E318G] carriers, suggesting a peculiar biochemical effect of this mutation.
authors.affiliation: Department of Neuroscience, Mario Negri Institute for Pharmacological Research, via Eritrea 62, 20157 Milan, Italy. albani@marionegri.it
authors.forename: Diego
authors.initials: D
authors.lastname: Albani
authors.forename: Ignazio
authors.initials: I
authors.lastname: Roiter
authors.forename: Vladimiro
authors.initials: V
authors.lastname: Artuso
authors.forename: Sara
authors.initials: S
authors.lastname: Batelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Prato
authors.forename: Marzia
authors.initials: M
authors.lastname: Pesaresi
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.forename: Amalia
authors.initials: A
authors.lastname: Bruni
authors.forename: Massimo
authors.initials: M
authors.lastname: Franceschi
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Piras
authors.forename: Annamaria
authors.initials: A
authors.lastname: Confaloni
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D019943:Amino Acid Substitution / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D006580:Genetic Carrier Screening; D018698:Glutamic Acid / Q000235:genetics; D005998:Glycine / Q000235:genetics; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D053764:Presenilin-1 / Q000235:genetics*
chemical_list: D053764:Presenilin-1; D018698:Glutamic Acid; D005998:Glycine