Abstract
Mutations at codon 717 in exon 17 of the β–amyloid precursor protein (APP) gene have previously been shown to segregate with early onset Alzheimer's disease in some families. We have identified a double mutation at codons 670 and 671 (APP 770 transcript) in exon 16 which co–segregates with the disease in two large (probably related) early–onset Alzheimer's disease families from Sweden. Two base pair transversions (G to T, A to C) from the normal sequence predict Lys to Asn and Met to Leu amino acid substitutions at codons 670 and 671 of the APP transcript. This mutation occurs at the amino terminal of β–amyloid and may be pathogenic because it occurs at or close to the endosomal/lysosomal cleavage site of the molecule. Thus, pathogenic mutations in APP frame the β–amyloid sequence.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Masters, C.L. et al. Proc. natn. Acad. Sci. U.S.A. 82, 4245–4249 (1985).
Wong, C.W., Quaranta, V. & Glenner, G. Proc. natn. Acad. Sci. U.S.A. 82, 8729–8732 (1985).
Glenner, G. & Wong, C.W. Biochem. Biophys. Res. Comm. 120, 885–890 (1984).
Luyendijk, W. et al. J neurol. Sci. 85, 267–280 (1988).
Selkoe, D.J. Neuron 6, 487–491 (1991).
Yoshikai, S., Sasaki, H., Doh-ura, K., Furuya, H. & Sakaki, Y. Gene 87, 257–263 (1990).
Goate, A. et al. Nature 349, 704–706, (1991).
Murrell, J., Farlow, M., Ghetti, B. & Benson, M. Science 254, 97–99, (1991).
Chartier Harlin, M.C. et al. Nature 353, 844–846 (1991).
Naruse, S. et al. Lancet 337, 978–979 (1991).
Yoshioka, K. et al. Biochem. Biophys. Res. Comm. 178, 1141–1146 (1991).
Hardy, J. et al. Lancet 337, 1342–1343 (1991).
Van Broeckhoven, C.M. et al. Science 248, 1120–1122, (1990).
Levy, E. et al. Science 240, 1124–1128, (1990).
Hendricks, L. et al. Nature Genet. 1, 218–221 (1992).
Weeks, D.E., Ott, J. & Lathrop, G M. Am. J. hum. Genet. 47(3), A204 (1990).
McKhann, G et al. Neurology 34, 939–944, (1984).
Hardy, J. & Higgins, J. Science 256, 184–185, (1992).
Esch, F. et al. Science 248, 1122–1124 (1990).
Anderson, J.P. et al. Neurosci. Letts. 128, 126–128 (1991).
Estus, S. et al. Science 255, 726–728 (1992).
Golde, T., Estus, S., Younkin, L., Selkoe, D. & Younkin, S. Science 255, 728–730 (1992).
Tanzi, R.E. & Hyman, B.T. Nature 350, 564 (1991).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Mullan, M., Crawford, F., Axelman, K. et al. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid. Nat Genet 1, 345–347 (1992). https://doi.org/10.1038/ng0892-345
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0892-345
- Springer Nature America, Inc.
This article is cited by
-
Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion
Acta Neuropathologica Communications (2024)
-
A novel mouse model for N-terminal truncated Aβ2-x generation through meprin β overexpression in astrocytes
Cellular and Molecular Life Sciences (2024)
-
Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity
Acta Neuropathologica Communications (2023)
-
Comprehensive genetic screening of early-onset dementia patients in an Austrian cohort-suggesting new disease-contributing genes
Human Genomics (2023)
-
Alternative splicing in neurodegenerative disease and the promise of RNA therapies
Nature Reviews Neuroscience (2023)