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 exon 9 (Δ9) from the mRNA transcript. This germline mutation results in a similar alteration in mRNA level as previously described with the variant AD and the Δ9 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.
Similar content being viewed by others
Article PDF
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hiltunen, M., Helisalmi, S., Mannermaa, A. et al. 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?. Eur J Hum Genet 8, 259–266 (2000). https://doi.org/10.1038/sj.ejhg.5200423
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.ejhg.5200423
Keywords
This article is cited by
-
Dissecting the clinical heterogeneity of early-onset Alzheimer’s disease
Molecular Psychiatry (2022)
-
Genetics of dementia in a Finnish cohort
European Journal of Human Genetics (2018)
-
Presenilin-1 Delta E9 Mutant Induces STIM1-Driven Store-Operated Calcium Channel Hyperactivation in Hippocampal Neurons
Molecular Neurobiology (2018)
-
17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression
Molecular Psychiatry (2017)
-
Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin–1 gene
Journal of Neurology (2006)