title: Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant.
abstract: Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 were sought by direct nucleotide sequence analysis of the open reading frame of 60 pedigrees with familial Alzheimer's disease (FAD). In the majority of these pedigrees, PS-1 and beta-amyloid precursor protein (beta APP) gene mutations had been excluded. While no additional PS-2 pathogenic mutations were detected, four silent nucleotide substitutions and alternative splicing of nucleotides 1338-1340 (Glu325) were observed. Analysis of additional members of a pedigree known to segregate a Met239Val mutation in PS-2 revealed that the age of onset of symptoms is highly variable (range 45-88 years). This variability is not attributable to differences in ApoE genotypes. These results suggest (i) that, in contrast to mutations in PS-1, mutations in PS-2 are a relatively rare cause of FAD; (ii) that other genetic or environmental factor modify the AD phenotype associated with PS-2 mutations; and (iii) that still other FAD susceptibility genes remain to be identified.
authors.affiliation: Department of Medicine, University of Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Sherrington
authors.forename: S
authors.initials: S
authors.lastname: Froelich
authors.forename: S
authors.initials: S
authors.lastname: Sorbi
authors.forename: D
authors.initials: D
authors.lastname: Campion
authors.forename: H
authors.initials: H
authors.lastname: Chi
authors.forename: E A
authors.initials: EA
authors.lastname: Rogaeva
authors.forename: G
authors.initials: G
authors.lastname: Levesque
authors.forename: E I
authors.initials: EI
authors.lastname: Rogaev
authors.forename: C
authors.initials: C
authors.lastname: Lin
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
authors.forename: M
authors.initials: M
authors.lastname: Ikeda
authors.forename: L
authors.initials: L
authors.lastname: Mar
authors.forename: A
authors.initials: A
authors.lastname: Brice
authors.forename: Y
authors.initials: Y
authors.lastname: Agid
authors.forename: M E
authors.initials: ME
authors.lastname: Percy
authors.forename: F
authors.initials: F
authors.lastname: Clerget-Darpoux
authors.forename: S
authors.initials: S
authors.lastname: Piacentini
authors.forename: G
authors.initials: G
authors.lastname: Marcon
authors.forename: B
authors.initials: B
authors.lastname: Nacmias
authors.forename: L
authors.initials: L
authors.lastname: Amaducci
authors.forename: T
authors.initials: T
authors.lastname: Frebourg
authors.forename: L
authors.initials: L
authors.lastname: Lannfelt
authors.forename: J M
authors.initials: JM
authors.lastname: Rommens
authors.forename: P H
authors.initials: PH
authors.lastname: St George-Hyslop
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D053766:Presenilin-2
chemical_list: D001057:Apolipoproteins E; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2