title: Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.
abstract: We report the cloning of a novel gene (E5-1) encoded on chromosome 1 which has substantial nucleotide and amino-acid sequence similarity to the S182 gene on chromosome 14q24.3. Mutations, including three new missense mutations in the S182 gene, are associated with the AD3 subtype of early-onset familial Alzheimer's disease (AD). Both the E5-1 and the S182 proteins are predicted to be integral membrane proteins with seven membrane-spanning domains, and a large exposed loop between the sixth and seventh transmembrane domains. Analysis of the nucleotide sequence of the open reading frame (ORF) of the E5-1 gene led to the discovery of two missense substitutions at conserved amino-acid residues in affected members of pedigrees with a form of familial AD that has a later age of onset than the AD3 subtype (50-70 years versus 30-60 years for AD3). These observations imply that the E5-1 gene on chromosome 1 and the S182 gene on chromosome 14q24.3 are members of a family of genes (presenilins) with related functions, and indicates that mutations in conserved residues of E5-1 could also play a role in the genesis of AD. Our results also indicate that still other AD susceptibility genes exist.
authors.affiliation: Department of Medicine (Neurology), University of Toronto, Ontario, Canada.
authors.forename: E I
authors.initials: EI
authors.lastname: Rogaev
authors.forename: R
authors.initials: R
authors.lastname: Sherrington
authors.forename: E A
authors.initials: EA
authors.lastname: Rogaeva
authors.forename: G
authors.initials: G
authors.lastname: Levesque
authors.forename: M
authors.initials: M
authors.lastname: Ikeda
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
authors.forename: H
authors.initials: H
authors.lastname: Chi
authors.forename: C
authors.initials: C
authors.lastname: Lin
authors.forename: K
authors.initials: K
authors.lastname: Holman
authors.forename: T
authors.initials: T
authors.lastname: Tsuda
mesh_terms: D000544:Alzheimer Disease / Q000145:classification / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002878:Chromosomes, Human, Pair 1; D004247:DNA; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation; D053764:Presenilin-1; D053766:Presenilin-2; D017386:Sequence Homology, Amino Acid
chemical_list: D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D004247:DNA