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Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease

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Abstract

Some cases of Alzheimer's disease are inherited as an autosomal dominant trait. Genetic linkage studies have mapped a locus (AD3) associated with susceptibility to a very aggressive form of Alzheimer's disease to chromosome 14q24.3. We have defined a minimal cosegregating region containing the AD3 gene, and isolated at least 19 different transcripts encoded within this region. One of these transcripts (S182) corresponds to a novel gene whose product is predicted to contain multiple transmembrane domains and resembles an integral membrane protein. Five different missense mutations have been found that cosegregate with early-onset familial Alzheimer's disease. Because these changes occurred in conserved domains of this gene, and are not present in normal controls, they are likely to be causative of AD3.

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Author notes

  1. P. H. St George-Hyslop: To whom correspondence should be addressed

Authors and Affiliations

  1. Centre for Research into Neurodegenerative Diseases, Departments of Medicine (Neurology) and Medical Biophysics, University of Toronto, Toronto, and Department of Medicine, Division of Neurology, The Toronto Hospital, Toronto, Ontario, M5S 1A8, Canada

    R. Sherrington, E. I. Rogaev, Y. Liang, E. A. Rogaeva, G. Levesque, M. Ikeda, H. Chi, C. Lin, G. Li, K. Holman, T. Tsuda, P. E. Fraser & P. H. St George-Hyslop

  2. Research Institute, The Hospital for Sick Children, and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada

    L. Mar & J. M. Rommens

  3. Laboratoire de Neurohistologie, Ecole Pratique des Hautes Etudes and U106, INSERM La Salpetriere, 75651, Paris, Cedex 13, France

    J.-F. Foncin

  4. USL-6 and UO-CNR, 88046, Lamezia Terme, Italy

    A. C. Bruni & M. P. Montesi

  5. Department of Neurology and Psychiatry, University of Florence, viale Morgagni 85, Florence, Italy

    S. Sorbi

  6. Department of Neurology, University of Turin, via Cherasco 15, 10126, Turin, Italy

    I. Rainero & L. Pinessi

  7. Clinical Neuropharmaeology Section, NINDS, 9000 Rockville Pike, Bethesda, Maryland, 20892, USA

    L. Nee

  8. Centre d'Etude Polymorphisme Humaine, 27 Rue Juliette Dodu, 75010, Paris, France

    I. Chumakov

  9. Department of Neurology, University of Massachusetts Medical Center, 55 Lake Avenue, Worcester, Massachusetts, 01655, USA

    D. Pollen

  10. Molecular Neurogenetics Laboratory and Laboratory of Genetics and Aging, Massachusetts General Hospital, Departments of Neurology and Genetics, Harvard Medical School, Boston, Massachusetts, 02114, USA

    W. Wasco, J. L. Haines & R. E. Tanzi

  11. Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, North Carolina, 27710, USA

    H. A. R. Da Silva, M. A. Pericak-Vance & A. D. Roses

  12. Molecular Pathology, Glaxo Research and Development, Greenford Road, Greenford, Middlesex, UB6 OHE, UK

    P. Sanseau

  13. Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, 59 Route 10, East Hanover, New Jersey, 07936, USA

    R. J. Polinsky

  14. MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh, UK

    A. Brookes

Authors
  1. R. Sherrington
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  2. E. I. Rogaev
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  3. Y. Liang
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  4. E. A. Rogaeva
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  5. G. Levesque
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  6. M. Ikeda
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  7. H. Chi
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  8. C. Lin
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  9. G. Li
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  10. K. Holman
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  11. T. Tsuda
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  12. L. Mar
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  13. J.-F. Foncin
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  14. A. C. Bruni
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  15. M. P. Montesi
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  16. S. Sorbi
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  17. I. Rainero
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  18. L. Pinessi
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  19. L. Nee
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  20. I. Chumakov
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  21. D. Pollen
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  22. A. Brookes
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  23. P. Sanseau
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  24. R. J. Polinsky
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  25. W. Wasco
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  26. H. A. R. Da Silva
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  27. J. L. Haines
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  28. M. A. Pericak-Vance
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  29. R. E. Tanzi
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  30. A. D. Roses
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  31. P. E. Fraser
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  32. J. M. Rommens
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  33. P. H. St George-Hyslop
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Sherrington, R., Rogaev, E., Liang, Y. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754–760 (1995). https://doi.org/10.1038/375754a0

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  • DOI: https://doi.org/10.1038/375754a0

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