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

• Letter
• Published: 05 December 1996
• Naohisa Oda3,
• Pamela J. Kaisaki1,2,
• Stephan Menzel1,2,
• Hiroto Furuta3,
• Martine Vaxillaire4,5,
• Lorraine Southam4,
• Roger D. Cox4,
• G. Mark Lathrop4,
• V. Vicky Boriraj1,
• Xiangna Chen2,
• Nancy J. Cox3,
• Yukie Oda2,
• Hideki Yano2,
• Michelle M. Le Beau3,
• Shirou Yamada6,
• Hidekazu Nishigori6,
• Jun Takeda6,
• Stefan S. Fajans7,
• Andrew T. Hattersley8,
• Naoko Iwasaki9,
• Torben Hansen10,
• Oluf Pedersen10,
• Kenneth S. Polonsky3,
• Robert C. Turner11,
• Gilberto Velho12,
• Jean-Claude Chèvre5,
• Philippe Froguel5 &
• …
• Graeme I. Bell1,2,3

Nature volume 384, pages 455–458 (1996)Cite this article

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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.

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Authors and Affiliations

1. Howard Hughes Medical Institute, The University of Chicago, 5841 South Maryland Avenue, MC1028, Chicago, Illinois, 60637, USA
   Kazuya Yamagata, Pamela J. Kaisaki, Stephan Menzel, V. Vicky Boriraj & Graeme I. Bell
2. Department of Biochemistry & Molecular Biology, The University of Chicago, 5841 South Maryland Avenue, MC1028, Chicago, Illinois, 60637, USA
   Kazuya Yamagata, Pamela J. Kaisaki, Stephan Menzel, Xiangna Chen, Yukie Oda, Hideki Yano & Graeme I. Bell
3. Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, MC1028, Chicago, Illinois, 60637, USA
   Naohisa Oda, Hiroto Furuta, Nancy J. Cox, Michelle M. Le Beau, Kenneth S. Polonsky & Graeme I. Bell
4. Wellcome Trust Centre for Human Genetics, Windmill Road, Oxford, OX3 7BN, UK
   Martine Vaxillaire, Lorraine Southam, Roger D. Cox & G. Mark Lathrop
5. CNRS EP10 Institut Pasteur de Lille, 59019, Lille, France
   Martine Vaxillaire, Jean-Claude Chèvre & Philippe Froguel
6. Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, 371, Japan
   Shirou Yamada, Hidekazu Nishigori & Jun Takeda
7. Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, 48109, USA
   Stefan S. Fajans
8. Department of Vascular Medicine and Diabetes Research, Postgraduate Medical School, University of Exeter, Exeter, EX2 5AX, UK
   Andrew T. Hattersley
9. Diabetes Center, Tokyo Women's Medical College, Tokyo, 162, Japan
   Naoko Iwasaki
10. Steno Diabetes Center, DK-2820, Gentofte, Denmark
    Torben Hansen & Oluf Pedersen
11. Diabetes Research Laboratories, Radcliffe Infirmary, Oxford, OX2 6HE, UK
    Robert C. Turner
12. INSERM U-358, Hôpital Saint-Louis, 75010, Paris, France
    Gilberto Velho

Authors

1. Kazuya Yamagata
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2. Naohisa Oda
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3. Pamela J. Kaisaki
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4. Stephan Menzel
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5. Hiroto Furuta
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6. Martine Vaxillaire
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7. Lorraine Southam
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8. Roger D. Cox
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9. G. Mark Lathrop
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10. V. Vicky Boriraj
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11. Xiangna Chen
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12. Nancy J. Cox
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13. Yukie Oda
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14. Hideki Yano
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15. Michelle M. Le Beau
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16. Shirou Yamada
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17. Hidekazu Nishigori
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18. Jun Takeda
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19. Stefan S. Fajans
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20. Andrew T. Hattersley
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21. Naoko Iwasaki
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22. Torben Hansen
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23. Oluf Pedersen
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24. Kenneth S. Polonsky
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25. Robert C. Turner
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26. Gilberto Velho
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27. Jean-Claude Chèvre
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28. Philippe Froguel
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29. Graeme I. Bell
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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

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• Received: 26 September 1996
• Accepted: 05 November 1996
• Issue Date: 05 December 1996
• DOI: https://doi.org/10.1038/384455a0

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