title: Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer's disease family: an Alu core sequence-stimulated recombination?
abstract: Mutations in the presenilin-1 (PS-1) gene have been shown to cause early onset Alzheimer's disease (EOAD) in an autosomal dominant manner. We have identified a novel 4.6-kb genomic deletion in the PS-1 gene in a Finnish EOAD family, which leads to an inframe exclusion of exon9 (delta9) from the mRNA transcript. This germline mutation results in a similar alteration in mRNA level as previously described with the variant AD and the delta9 splice-site mutations. In this present EOAD family, the clinical and neuropathological phenotype of patients are those of the typical AD without indications of spastic paraparesis or 'cotton wool' plaques, which are the hallmarks of the variant AD. A sequence analysis of the deletion crossover site of the mutant and corresponding wild type regions revealed complete homology with the recombigenic 26 bp Alu core sequence at intron 8. In addition, a segment at the intron 9 breakpoint displayed homology with the core sequence, but comparison of the 5' and 3' breakpoint sequences did not reveal significant identity favouring involvement of Alu core sequence-stimulated non-homologous recombination rather than Alu-mediated homologous pairing of the fragments. This study shows that large genomic rearrangements can affect the EOAD gene PS-1 through a mechanism, which may involve Alu core sequence-stimulated recombination.
authors.affiliation: Department of Neurology, University Hospital and University of Kuopio, Finland. mhiltune@messi.uku.fi
authors.forename: M
authors.initials: M
authors.lastname: Hiltunen
authors.forename: S
authors.initials: S
authors.lastname: Helisalmi
authors.forename: A
authors.initials: A
authors.lastname: Mannermaa
authors.forename: I
authors.initials: I
authors.lastname: Alafuzoff
authors.forename: A M
authors.initials: AM
authors.lastname: Koivisto
authors.forename: M
authors.initials: M
authors.lastname: Lehtovirta
authors.forename: M
authors.initials: M
authors.lastname: Pirskanen
authors.forename: R
authors.initials: R
authors.lastname: Sulkava
authors.forename: A
authors.initials: A
authors.lastname: Verkkoniemi
authors.forename: H
authors.initials: H
authors.lastname: Soininen
mesh_terms: D017668:Age of Onset; D020087:Alu Elements / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000032:analysis; D001483:Base Sequence; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics*; D005192:Family Health; D005260:Female; D005387:Finland; D005625:Frontal Lobe / Q000737:chemistry / Q000473:pathology; D006239:Haplotypes; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D053764:Presenilin-1; D011995:Recombination, Genetic; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid
chemical_list: D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D004247:DNA