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.

  • Letter
  • Published:

Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3)

Abstract

THE disease non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is characterized by abnormally high blood glucose resulting from a relative deficiency of insulin1. It affects about 2% of the world's population and treatment of diabetes and its complications are an increasing health-care burden2. Genetic factors are important in the aetiology of NIDDM, and linkage studies are starting to localize some of the genes that influence the development of this disorder3. Maturity-onset diabetes of the young (MODY), a single-gene disorder responsible for 2–5% of NIDDM, is characterized by autosomal dominant inheritance and an age of onset of 25 years or younger4–6. MODY genes have been localized to chromosomes 7, 12 and 20 (refs 5, 7, 8) and clinical studies indicate that mutations in these genes are associated with abnormal patterns of glucose-stimulated insulin secretion1,9. The gene on chromosome 7 (MODY2) encodes the glycolytic enzyme glucokinase5 which plays a key role in generating the metabolic signal for insulin secretion and in integrating hepatic glucose uptake. Here we show that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1α (HNF-1α, which is encoded by the gene TCF1). HNF-1α is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes10,11 and also functions as a weak transactivator of the rat insulin-I gene12.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Polonsky, K. S. Diabetes 44, 705–717 (1995).

    Article  CAS  PubMed  Google Scholar 

  2. McCarty, D. S. & Zimmet, P. Diabetes 1994 to 2010: Global Estimates and Projections (International Diabetes Institute, Melbourne, Australia, 1994).

    Google Scholar 

  3. Hanis, C. L. et al. Nature Genet. 13, 161–166 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Fajans, S. S. Diabetes/Metabol. Rev. 5, 579–606 (1989).

    Article  CAS  Google Scholar 

  5. Froguel, P. et al. N. Engl. J. Med. 328, 697–702 (1993).

    Article  CAS  PubMed  Google Scholar 

  6. Ledermann, H. M. Lancet 345, 648 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Bell, G. I. et al. Proc. Natl Acad. Sci. USA 88, 1484–1488 (1991).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. Vaxillaire, M. et al. Nature Genet. 9, 418–423 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Byrne, M. M. et al. Diabetes 45, 1503–1510 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Frain, M. et al. Cell 59, 145–157 (1989).

    Article  CAS  PubMed  Google Scholar 

  11. Tronche, F. & Yaniv, M. Bioessays 14, 579–587 (1992).

    Article  CAS  PubMed  Google Scholar 

  12. Emens, L. A., Landers, D. W. & Moss, L. G. Proc. Natl Acad. Sci. USA 89, 7300–7304 (1992).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Menzel, S. et al. Diabetes 44, 1408–1413 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Chumakov, I. M. et al. Nature 377 (suppl.), 175–297 (1995).

    CAS  PubMed  Google Scholar 

  15. Hudson, T. J. et al. Science 270, 1945–1954 (1994).

    Article  ADS  Google Scholar 

  16. Church, D. M. et al. Nature Genet. 6, 98–105 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Korn, B. et al. Hum. Mol. Genet. 1, 235–242 (1992).

    Article  CAS  PubMed  Google Scholar 

  18. Kenny, S. J., Aubert, R. E. & Geiss, L. S. in Diabetes in America 2nd edn (eds National Diabetes Data Group) 47–67 (NIH publication no. 95-1468, 1995).

    Google Scholar 

  19. Mendel, D. B., Hansen, L. P., Graves, M. K., Conley, P. B. & Crabtree, G. R. Genes Dev. 5, 1042–1056 (1991).

    Article  CAS  PubMed  Google Scholar 

  20. Herskowitz, I. Nature 329, 219–222 (1987).

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Pontoglio, M. et al. Cell 84, 575–585 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Lesage, S. et al. Diabetes 44, 1243–1247 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Mahtani, M. et al. Nature Genet. 14, 90–94 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Byrne, M. M., Sturis, J., Sobel, R. J. & Polonsky, K. S. Am. J. Physiol. 270, E572–E579 (1996).

    CAS  PubMed  Google Scholar 

  25. Yamagata, K. et al. Nature 384, 458–460 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  26. Kuo, C. J. et al. Nature 355, 457–461 (1992).

    Article  ADS  CAS  PubMed  Google Scholar 

  27. Bach, I. et al. Genomics 8, 155–164 (1990).

    Article  CAS  PubMed  Google Scholar 

  28. Bach, I. & Yaniv, M. EMBO J. 12, 4229–4242 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bach, I., Pontoglio, M. & Yaniv, M. Nucleic Acids Res. 20, 4199–4204 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hörlein, A., Grajer, K.-H. & Igo-Kemenes, T. Biol. Chem. Hoppe-Seyler 374, 419–425 (1993).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamagata, K., Oda, N., Kaisaki, P. et al. Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3). Nature 384, 455–458 (1996). https://doi.org/10.1038/384455a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/384455a0

This article is cited by

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