title: Analysis of the 5' sequence, genomic structure, and alternative splicing of the presenilin-1 gene (PSEN1) associated with early onset Alzheimer disease.
abstract: Mutations in the human presenilin genes (PSEN1 and PSEN2) are associated with early onset familial Alzheimer disease. The presenilin genes encode integral membrane proteins with similar structures, which suggests that they may have closely related, but as yet unknown functions. Analysis of the 5' upstream sequence and the structure of the PSEN1 gene reveals that the 5' sequence contains multiple putative transcription regulatory elements including clusters of STAT elements involved in transcriptional activation in response to signal transduction. The first four exons contain untranslated sequences, with Exons 1 and 2 representing alternate initial transcription sites. The function of these alternate initial exons is unclear. Exon 4 bears the first ATG sequence. The last 12 bp of Exon 4 is used as an alternative splice donor site. Exon 9 is alternately spliced in leukocytes, but not in most other tissues. Splicing of Exon 9 is predicted to cause significant structural changes to the protein. The majority of transcripts expressed in most tissues are polyadenylated 1127 bp from the TAG stop codon in Exon 13. A small proportion of transcripts contain the same 5'UTR and ORF but are polyadenylated 4435 bp from the stop codon. The longer polyadenylated transcripts contain three additional palindromes and at least one additional stem-loop structure with stabilities greater than -16 kcal/mol.
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, M5S 3H2, Canada.
authors.forename: E I
authors.initials: EI
authors.lastname: Rogaev
authors.forename: R
authors.initials: R
authors.lastname: Sherrington
authors.forename: C
authors.initials: C
authors.lastname: Wu
authors.forename: G
authors.initials: G
authors.lastname: Levesque
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
authors.forename: E A
authors.initials: EA
authors.lastname: Rogaeva
authors.forename: M
authors.initials: M
authors.lastname: Ikeda
authors.forename: K
authors.initials: K
authors.lastname: Holman
authors.forename: C
authors.initials: C
authors.lastname: Lin
authors.forename: W J
authors.initials: WJ
authors.lastname: Lukiw
authors.forename: P J
authors.initials: PJ
authors.lastname: de Jong
authors.forename: P E
authors.initials: PE
authors.lastname: Fraser
authors.forename: J M
authors.initials: JM
authors.lastname: Rommens
authors.forename: P
authors.initials: P
authors.lastname: St George-Hyslop
mesh_terms: D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D015894:Genome, Human; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D053764:Presenilin-1; D017422:Sequence Analysis, DNA
chemical_list: D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1