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
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).
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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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