Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Katzman, R. N. Engl. J. Med. 314, 964–973 (1986).

    CAS  Article  Google Scholar 

  2. 2

    St George-Hyslop, P. H. et al. Nature 347, 194–197 (1991).

    Article  ADS  Google Scholar 

  3. 3

    Strittmatter, W. J. et al. Proc. natn. Acad. Sci. U.S.A. 90, 1977–1981 (1993).

    CAS  Article  ADS  Google Scholar 

  4. 4

    Saunders, A. et al. Neurology 43, 1467–1472 (1993).

    CAS  Article  Google Scholar 

  5. 5

    Goate, A. M. et al. Nature 349, 704–706 (1991).

    CAS  Article  ADS  Google Scholar 

  6. 6

    Chartier-Harlin, M.-C. et al. Nature 353, 844–846 (1991).

    CAS  Article  ADS  Google Scholar 

  7. 7

    Murrell, J., Farlow, M., Ghetti, B. & Benson, M. D. Science 254, 97–99 (1991).

    CAS  Article  ADS  Google Scholar 

  8. 8

    Karlinsky, H. et al. Neurology 42, 1445–1453 (1992).

    CAS  Article  Google Scholar 

  9. 9

    Schellenberg, G. D. et al. Science 258, 668–670 (1992).

    CAS  Article  ADS  Google Scholar 

  10. 10

    St George-Hyslop, P. et al. Nature Genet. 2, 330–334 (1992).

    CAS  Article  Google Scholar 

  11. 11

    Van Broeckhoven, C. et al. Nature Genet. 2, 335–339 (1992).

    CAS  Article  Google Scholar 

  12. 12

    Rogaev, E. I. et al. Neurology 43, 2275–2279 (1993).

    CAS  Article  Google Scholar 

  13. 13

    Wong, L. et al. Neurosci. Lett. 152, 96–98 (1993).

    CAS  Article  Google Scholar 

  14. 14

    Nee, L. et al. Archs Neurol. 40, 203–208 (1983).

    CAS  Article  Google Scholar 

  15. 15

    Frommelt, P., Schnabel, R., Kuhne, W., Nee, L. E. & Polinsky, R. J. Alzheimer Dis. Ass. Disorders 5, 36–43 (1991).

    CAS  Article  Google Scholar 

  16. 16

    Goudsmit, J. et al. J. neurol. Sci. 49, 78–89 (1981).

    Article  Google Scholar 

  17. 17

    Pollen, D. Hannah's Heirs: the Quest for the Genetic Origins of Alzheimer's Disease (Oxford Univ. Press, Oxford, 1993).

    Google Scholar 

  18. 18

    Foncin, J.-F. et al. Rev. Neurol. 141, 194–202 (1985).

    CAS  PubMed  Google Scholar 

  19. 19

    Bergamini, L. et al. Acta neurol. 13, 534–538 (1991).

    CAS  Google Scholar 

  20. 20

    Pericak-Vance, M. A., Yamoaka, L. H. & Haynes, C. S. Expl Neurol. 102, 271–279 (1988).

    CAS  Article  Google Scholar 

  21. 21

    Cruts, M. et al. Neurobiol Aging 15, S129 (1994).

    Google Scholar 

  22. 22

    Kerem, B.-S. et al. Science 245, 1073–1080 (1989).

    CAS  Article  ADS  Google Scholar 

  23. 23

    Gusella, J. F. & Group, H. D. C. Cell 72, 971–983 (1993).

    Article  Google Scholar 

  24. 24

    Rommens, J. M. et al. Hum. molec. Genet. 2, 901–907 (1993).

    CAS  Article  Google Scholar 

  25. 25

    Saleeba, J. A. & Cotton, R. G. Meth. Enzym. 217, 285–295 (1993).

    Google Scholar 

  26. 26

    Liu, Q. & Sommer, S. S. BioTechniques 18, 470–476 (1995).

    CAS  PubMed  Google Scholar 

  27. 27

    Kozak, M. J. biol. Chem. 266, 19867–19870 (1991).

    CAS  PubMed  Google Scholar 

  28. 28

    Rost, B. & Sander, C. Proteins 19, 55–72 (1994).

    CAS  Article  Google Scholar 

  29. 29

    Kyte, J. & Doolittle, R. F. J. molec. Biol. 157, 105 (1982).

    CAS  Article  Google Scholar 

  30. 30

    Altschul, S. F., Gish, W., Miller, W., Myers, E. W. & Lipman, D. J. molec. Biol. 215, 403–410 (1990).

    CAS  Article  Google Scholar 

  31. 31

    L'Hernault, S. W. L. & Arduengo, P. M. J. Cell Biol. 119, 55–69 (1992).

    CAS  Article  Google Scholar 

  32. 32

    Schellenberg, G. D. et al. Am. J. hum. Genet. 53, 619–628 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    St George-Hyslop, P. H. et al. Science 263, 536–537 (1994).

    Article  ADS  Google Scholar 

  34. 34

    Kosik, K. & Greenberg, S. M. in Alzheimer Disease (eds Terry, R. D., Katzman, R. & Bick, K. L.) 335–344 (Raven, New York, 1994).

    Google Scholar 

  35. 35

    Selkoe, D. J. A. Rev. Neurosci. 17, 489–517 (1994).

    CAS  Article  Google Scholar 

  36. 36

    MacLennan, D. H. et al. Nature 343, 559–561 (1990).

    CAS  Article  ADS  Google Scholar 

  37. 37

    Ptacek, L. J. et al. Cell 67, 1021–1027 (1991).

    CAS  Article  Google Scholar 

  38. 38

    Chalfie, M. & Wolinsky, E. Nature 345, 410–416 (1990).

    CAS  Article  ADS  Google Scholar 

  39. 39

    Driscoll, M. & Chalfie, M. Nature 349, 588–593 (1991).

    CAS  Article  ADS  Google Scholar 

  40. 40

    Etcheberrigaray, R. et al. Proc. natn. Acad. Sci. U.S.A. 90, 8209–8213 (1994).

    Article  ADS  Google Scholar 

  41. 41

    Mattson, M. P. et al. Trends Neurosci. 16, 409–414 (1993).

    CAS  Article  Google Scholar 

  42. 42

    Querfurth, H. W. & Selkoe, D. J. Biochemistry 33, 4550–4561 (1994).

    CAS  Article  Google Scholar 

  43. 43

    Weissenbach, J. et al. Nature 359, 794–798 (1992).

    CAS  Article  ADS  Google Scholar 

  44. 44

    NIH/CEPH Collaborative Mapping Group. Science 258, 67–86 (1992).

  45. 45

    Gyapay, G. et al. Nature Genet. 7, 246–339 (1994).

    CAS  Article  Google Scholar 

  46. 46

    Albertsen, H. M. et al. Proc. natn. Acad. Sci. U.S.A. 87, 4256–4260 (1990).

    CAS  Article  ADS  Google Scholar 

  47. 47

    Chumakov, I. M. et al. Nature Genet. 1, 222–225 (1992).

    CAS  Article  Google Scholar 

  48. 48

    Ioannu, P. A. et al. Nature Genet. 6, 84–89 (1994).

    Article  Google Scholar 

  49. 49

    Chumakov, I. et al. Nature 359, 380–387 (1992).

    CAS  Article  ADS  Google Scholar 

  50. 50

    Riley, J. et al. Nucleic Acids Res. 18, 2887–2890 (1990).

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing