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Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease

Nature volume 349, pages 704–706 (1991)Cite this article

Abstract

A LOCUS segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21 (ref. 1), close to the amyloid precursor protein (APP) gene2–5. Recombinants between the APP gene and the AD locus have been reported6–8 which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous9. Families with late-onset AD do not show linkage to chromosome 21 markers9,10. Some families with early-onset AD show linkage to chromosome 21 markers, but some do not8,9,11. This has led to the suggestion that there is non-allelic genetic heterogeneity even within early onset familial AD8,9. To avoid the problems that heterogeneity poses for genetic analysis, we have examined the cosegregation of AD and markers along the long arm of chromosome 21 in a single family with AD confirmed by autopsy. Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val→Ile) close to the carboxy terminus of the β-amyloid peptide. Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene.

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Author information

Author notes

  1. Andrew Haynes

    Present address: Department of Respiratory Medicine, St Mary's Hospital Medical School, London, W2 1PG, UK

  2. Louise James

    Present address: ICI Biotechnology Division, Alderley Park, Macclesfield, Cheshire, UK

  3. John Hardy: To whom correspondence should be addressed.

Authors and Affiliations

  1. Alzheimer's Disease Research Group, Departments of Biochemistry and Neurology, St Mary's Hospital Medical School, London, W2 1PG, UK

    Alison Goate, Marie-Christine Chartier-Harlin, Mike Mullan, Jeremy Brown, Fiona Crawford, Liana Fidani, Nick Irving, Phillippa Newton, Karen Rooke, Penelope Roques, Chris Talbot, Robert Williamson, Martin Rossor & John Hardy

  2. Department of Human Genetics, Yale University Medical School, 333 Cedar Street, New Haven, Connecticut, 06150, USA

    Luis Giuffra

  3. Duke University Medical Center, Durham, North Carolina, NC 27710, USA

    Margaret Pericak-Vance & Alien Roses

  4. Departments of Psychological Medicine and Medical Genetics, University of Wales College of Medicine, Cardiff, CF4 4XN, UK

    Rebecca Mant & Mike Owen

Authors
  1. Alison Goate
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Goate, A., Chartier-Harlin, MC., Mullan, M. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704–706 (1991). https://doi.org/10.1038/349704a0

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