Abstract
WE report the cloning of a novel gene (E5-1) encoded on chromosome 1 which has substantial nucleotide and amino-acid sequence similarity to the S182 gene on chromosome 14q24.3. Mutations, including three new missense mutations in the S182 gene, are associated with the AD3 subtype of early-onset familial Alzheimer's disease (AD)1. Both the E5-1 and the S182 proteins are predicted to be integral membrane proteins with seven membrane-spanning domains, and a large exposed loop between the sixth and seventh transmembrane domains. Analysis of the nucleotide sequence of the open reading frame (ORF) of the E5-1 gene led to the discovery of two missense substitutions at conserved amino-acid residues in affected members of pedigrees with a form of familial AD that has a later age of onset than the AD3 subtype (50–70 years versus 30–60 years for AD3). These observations imply that the E5-1 gene on chromosome 1 and the S182 gene on chromosome 14q24.3 are members of a family of genes (presenilins) with related functions, and indicates that mutations in conserved residues of E5-1 could also play a role in the genesis of AD. Our results also indicate that still other AD susceptibility genes exist.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Sherrington, R. et al. Nature 375, 754–760 (1995).
Altschul, S. F., Gish, W., Miller, W., Myers, E. W. & Lipman, D. J. molec. Biol. 215, 403–410 (1990).
Schellenberg, G. D. et al. Science 258, 668–670 (1992).
Lannfelt, L. et al. Nature Genet. 4, 218–219 (1993).
Katzman, R. & Kawas, C. in Alzheimer Disease (eds Terry, R. D., Katzman, R. & Bick, K. L.) 105–122 (Raven, New York, 1994).
Cook, R. H. et al. J. Neurology 29, 1402–1412 (1979).
Bird, T. D. et al. Ann. Neurol. 23, 25–31 (1988).
Hollmann, N. & Heineman, S. A. Rev. Neurosci. 17, 31–108 (1994).
Kyte, J. & Doolittle, R. F. J. molec. Biol. 157, 105–132 (1982).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Rogaev, E., Sherrington, R., Rogaeva, E. et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 376, 775–778 (1995). https://doi.org/10.1038/376775a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/376775a0
This article is cited by
-
The advent of Alzheimer treatments will change the trajectory of human aging
Nature Aging (2024)
-
Aberrant palmitoylation caused by a ZDHHC21 mutation contributes to pathophysiology of Alzheimer’s disease
BMC Medicine (2023)
-
Mechanisms of amyloid-β34 generation indicate a pivotal role for BACE1 in amyloid homeostasis
Scientific Reports (2023)
-
Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future
Signal Transduction and Targeted Therapy (2023)
-
Emerging diagnostics and therapeutics for Alzheimer disease
Nature Medicine (2023)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.