The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families

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Abstract

Genetic linkage studies place a gene causing early onset familial Alzheimer's disease (FAD) on chromosome 14q24.3 (refs 1–4). Five mutations within the S182 (Presenilin 1: PS–1) gene, which maps to this region, have recently been reported in several early onset FAD kindreds5. We have localized the PS-1 gene to a 75 kb region and present the structure of this gene, evidence for alternative splicing and describe six novel mutations in early onset FAD pedigrees all of which alter residues conserved in the STM26 (Presenilin 2: PS-2) gene.

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References

  1. 1

    Schellenberg, G. et al. Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science 258, 668–671 (1992).

  2. 2

    St. George-Hyslop, P. et al. Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14. Nature Genet. 2, 330–334 (1992).

  3. 3

    Van Broeckhoven, C. et al. Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3. Nature Genet. 2, 335–339 (1992).

  4. 4

    Mullan, M. et al. A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the α1-antichymotrypsin gene. Nature Genetics 2, 340–342 (1992).

  5. 5

    Sherrington, R. et al. Cloning of a gene bearing mis-sense mutations in early-onset familial Alzheimer's disease. Nature 375, 754–760 (1995).

  6. 6

    Levy-Lahad, E. et al. Candidate locus for the chromosome 1 familial Alzheimer's disease locus. Science 268, 973–977 (1995).

  7. 7

    Levy-Lahad, E. et al. A familial Alzheimer's disease locus on chromosome 1. Science 268, 970–972 (1995).

  8. 8

    Clark, R.F. et al. A yeast artificial chromosome contig from human chromosome 14q24 spanning the Alzheimer's disease locus, AD3. Hum. mol. Genet. (in the press).

  9. 9

    Hutton, M., Crook, R., Shaw, D. & Hardy, J. Exon trapping from a yeast artificial chromosome (YAC) that contains the cfos gene. Focus 17, 24–28 (1995).

  10. 10

    Grima, B. et al. A single human gene encoding multiple tyrosine hydroxylases with different predicted functional characteristics. Nature 326, 707–711 (1987).

  11. 11

    Bateson, A., Lasham, A. & Darlison, M. Gamma-aminobutyric acid A receptor heterogeneity is increased by alternative splicing of a novel beta-subunit gene transcript. J. Neurochem. 56, 1437–1440 (1991).

  12. 12

    Song, X.H. et al. Plasma amyloid β protein (Aβ) ending at Aβ42(43) is increased in carriers of familial AD linked to chromosome 14. Soc. Neurosci. Abtsr. (in the press).

  13. 13

    Haltia, M. et al. Chromosome 14-encoded Alzheimer's disease: Genetic and clinteopathological description. Annals Neurol. 36, 362–367 (1994).

  14. 14

    Kere, J. et al. Mapping human chromosomes by walking with sequence-tagged sites from yeast artificial chromosome inserts. Genomics 14, 241–248 (1992).

  15. 15

    Mueller, P. & Wold, B. In vivo footprinting of muscle-specific enhancer by ligation-mediated PCR. Science 246, 780–786 (1989).

  16. 16

    Srivastava, A., Montanaro, V. & Kere, J. Simplified template preparation and improved direct sequencing using Taq polymerase. PCR Methods Appl. 1, 255–256 (1992).

  17. 17

    Cohen, D., Chumakov, I. & Weissenbach, J. A first-generation physical map of the human genome. Nature 366, 698–701 (1993).

  18. 18

    Weissenbach, J. et al. A second-generation linkage map of the human genome. Nature 359, 794–801 (1992).

  19. 19

    Gynapay, G. et al. The 1993-94 Genethon human genetic linkage map. Nature Genet. 7, 246–339 (1994).

  20. 20

    Auffray, C. et al. IMAGE: integration au niveau moleculaire de ('analyse du genome humain et de son expression. C. R. Acad. des Sciences III 318, 263–272 (1995).

  21. 21

    Hawkins, T.L., O'Connor-Morin, T., Roy, A. & Santillan, C. DNA purification and isolation using a solid-phase. Nucl. Acids Res. 22, 4543–4544 (1994).

  22. 22

    Adams, M.D. et al. A model for high-throughput automated DMA sequencing and analysis core facilities. Nature 368, 474–475 (1994).

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Clark, R., Hutton, M., Fuldner, M. et al. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet 11, 219–222 (1995) doi:10.1038/ng1095-219

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