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A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid

Nature Genetics volume 1, pages 345–347 (1992)Cite this article

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.

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References

  1. Masters, C.L. et al. Proc. natn. Acad. Sci. U.S.A. 82, 4245–4249 (1985).

    Article  CAS  Google Scholar 

  2. Wong, C.W., Quaranta, V. & Glenner, G. Proc. natn. Acad. Sci. U.S.A. 82, 8729–8732 (1985).

    Article  CAS  Google Scholar 

  3. Glenner, G. & Wong, C.W. Biochem. Biophys. Res. Comm. 120, 885–890 (1984).

    Article  CAS  Google Scholar 

  4. Luyendijk, W. et al. J neurol. Sci. 85, 267–280 (1988).

    Article  CAS  Google Scholar 

  5. Selkoe, D.J. Neuron 6, 487–491 (1991).

    Article  CAS  Google Scholar 

  6. Yoshikai, S., Sasaki, H., Doh-ura, K., Furuya, H. & Sakaki, Y. Gene 87, 257–263 (1990).

    Article  CAS  Google Scholar 

  7. Goate, A. et al. Nature 349, 704–706, (1991).

    Article  CAS  Google Scholar 

  8. Murrell, J., Farlow, M., Ghetti, B. & Benson, M. Science 254, 97–99, (1991).

    Article  CAS  Google Scholar 

  9. Chartier Harlin, M.C. et al. Nature 353, 844–846 (1991).

    Article  CAS  Google Scholar 

  10. Naruse, S. et al. Lancet 337, 978–979 (1991).

    Article  CAS  Google Scholar 

  11. Yoshioka, K. et al. Biochem. Biophys. Res. Comm. 178, 1141–1146 (1991).

    Article  CAS  Google Scholar 

  12. Hardy, J. et al. Lancet 337, 1342–1343 (1991).

    Google Scholar 

  13. Van Broeckhoven, C.M. et al. Science 248, 1120–1122, (1990).

    Article  CAS  Google Scholar 

  14. Levy, E. et al. Science 240, 1124–1128, (1990).

    Article  Google Scholar 

  15. Hendricks, L. et al. Nature Genet. 1, 218–221 (1992).

    Article  Google Scholar 

  16. Weeks, D.E., Ott, J. & Lathrop, G M. Am. J. hum. Genet. 47(3), A204 (1990).

    Google Scholar 

  17. McKhann, G et al. Neurology 34, 939–944, (1984).

    Article  CAS  Google Scholar 

  18. Hardy, J. & Higgins, J. Science 256, 184–185, (1992).

    Article  CAS  Google Scholar 

  19. Esch, F. et al. Science 248, 1122–1124 (1990).

    Article  CAS  Google Scholar 

  20. Anderson, J.P. et al. Neurosci. Letts. 128, 126–128 (1991).

    Article  CAS  Google Scholar 

  21. Estus, S. et al. Science 255, 726–728 (1992).

    Article  CAS  Google Scholar 

  22. Golde, T., Estus, S., Younkin, L., Selkoe, D. & Younkin, S. Science 255, 728–730 (1992).

    Article  CAS  Google Scholar 

  23. Tanzi, R.E. & Hyman, B.T. Nature 350, 564 (1991).

    Article  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. Alzheimer's Disease Research Laboratories, Suncoast Gerontology Center and Department of Psychiatry, University of South Florida, Tampa, Florida, 33613, USA

    Mike Mullan & Fiona Crawford

  2. Karolinska Institute, Alzheimer's Disease Research Center, Department of Geriatric Medicine, Huddinge University Hospital, Sweden

    Karin Axelman, Lena Lilius, Bengt Winblad & Lars Lannfelt

  3. Department of Biochemistry, St Mary's Hospital Medical School, London, W2 1PG, UK

    Henry Houlden

Authors
  1. Mike Mullan
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  2. Fiona Crawford
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  3. Karin Axelman
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  4. Henry Houlden
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  5. Lena Lilius
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  6. Bengt Winblad
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  7. Lars Lannfelt
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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

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  • DOI: https://doi.org/10.1038/ng0892-345

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