title: E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles.
abstract: A single base substitution of a glutamic acid to an alanine codon 280 was found in the presenilin-1 (PS-1) gene on chromosome 14 in affected individuals in each of seven Colombian early-onset Alzheimer's disease (AD) kindreds. The mutation segregated with disease in kindreds tested. In the largest kindred (C2), the maximum two-point lod score between the mutation and AD was Z = 8.14 at theta = 0. The presence of a single mutation and the common geographic origin, with all families from the state of Antioquia, suggest a founder effect in this population. This finding is supported by the observation of a rare haplotype inherited with AD in all kindreds. These kindreds form the largest collection of AD cases with the same PS-1 mutation and the same educational, environmental, and ethnic background in which to study the phenotypic effect of putative risk factors, such as the epsilon4 allele of apolipoprotein E (ApoE) or head trauma. Of the few AD cases having a history of head trauma, the age of onset was not lowered. No effect of ApoE genotype on the age of onset was detected. Previous investigations of the effect of ApoE genotype on the age of onset were confounded by small patient numbers, familial clustering of ApoE genotypes, and combining data from unrelated families with different mutations.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Lendon
authors.forename: A
authors.initials: A
authors.lastname: Martinez
authors.forename: I M
authors.initials: IM
authors.lastname: Behrens
authors.forename: K S
authors.initials: KS
authors.lastname: Kosik
authors.forename: L
authors.initials: L
authors.lastname: Madrigal
authors.forename: J
authors.initials: J
authors.lastname: Norton
authors.forename: R
authors.initials: R
authors.lastname: Neuman
authors.forename: A
authors.initials: A
authors.lastname: Myers
authors.forename: F
authors.initials: F
authors.lastname: Busfield
authors.forename: M
authors.initials: M
authors.lastname: Wragg
authors.forename: M
authors.initials: M
authors.lastname: Arcos
authors.forename: J C
authors.initials: JC
authors.lastname: Arango Viana
authors.forename: J
authors.initials: J
authors.lastname: Ossa
authors.forename: A
authors.initials: A
authors.lastname: Ruiz
authors.forename: A M
authors.initials: AM
authors.lastname: Goate
authors.forename: F
authors.initials: F
authors.lastname: Lopera
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D004247:DNA / Q000097:blood; D004252:DNA Mutational Analysis; D018703:Founder Effect; D008040:Genetic Linkage; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D053764:Presenilin-1; D017422:Sequence Analysis, DNA
chemical_list: D001057:Apolipoproteins E; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D004247:DNA