title: Molecular analysis of the presenilin 1 (S182) gene in "sporadic" cases of Alzheimer's disease: identification and characterisation of unusual splice variants.
abstract: Mutations of the presenilin 1 (PS-1) gene at the Alzheimer's disease (AD) FAD3 locus on chromosome 14q24.3 are responsible for the majority of familial early-onset AD. As genes responsible for familial forms of AD are obvious candidates for further investigation in "sporadic" disease, we performed a molecular analysis of PS-1 transcripts extracted from brain tissues of a series of histologically confirmed cases of "sporadic" AD (n=10) and also from histologically "normal" (non-Alzheimer) age-matched brain controls (n=5). No sequence changes in the PS-1 coding sequence were detected after analysis by reverse transcription-PCR. This suggests that the frequency of mutations in the PS-1 (S182) coding region in "sporadic" Alzheimer's disease in very low. However, we demonstrated that the PS-1 gene is highly variably spliced. One splice variant involves the 5' untranslated region of the PS-1 gene only and hence encodes for normal PS-1. Six further splice variants involve coding regions of the PS-1 gene and result in truncated proteins lacking specific transmembrane domains. Most of these variants do not coincide with recognized sites of introns in the PS-1 gene. One of these variants, resulting in the loss of transmembrane domain TM-VII, was found only in an AD patient.
authors.affiliation: Molecular Medicine Unit, St. James's University Hospital, Leeds, England.
authors.forename: R
authors.initials: R
authors.lastname: Anwar
authors.forename: T P
authors.initials: TP
authors.lastname: Moynihan
authors.forename: H
authors.initials: H
authors.lastname: Ardley
authors.forename: N
authors.initials: N
authors.lastname: Brindle
authors.forename: P L
authors.initials: PL
authors.lastname: Coletta
authors.forename: N
authors.initials: N
authors.lastname: Cairns
authors.forename: A F
authors.initials: AF
authors.lastname: Markham
authors.forename: P A
authors.initials: PA
authors.lastname: Robinson
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics*; D001483:Base Sequence; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D053764:Presenilin-1; D012313:RNA / Q000032:analysis
chemical_list: D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012313:RNA