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Article
Nature Genetics  1, 345 - 347 (1992)
doi:10.1038/ng0892-345

A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N−terminus of bold beta−amyloid

Mike Mullan1, Fiona Crawford1, Karin Axelman2, Henry Houlden3, Lena Lilius2, Bengt Winblad2 & Lars Lannfelt2

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

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

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

Mutations at codon 717 in exon 17 of the beta−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 beta−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 beta−amyloid sequence.

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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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