A Hepatocyte Nuclear Factor-4α Gene (HNF4A) P2 Promoter Haplotype Linked With Late-Onset Diabetes

Studies of HNF4A Variants in the Norwegian MODY Registry

  1. Helge Ræder12,
  2. Lise Bjørkhaug12,
  3. Stefan Johansson12,
  4. Kjersti Mangseth12,
  5. Jørn V. Sagen13,
  6. Anne Hunting4,
  7. Ivar Følling5,
  8. Odd Johansen6,
  9. Marit Bjørgaas7,
  10. Povel N. Paus8,
  11. Oddmund Søvik1,
  12. Anders Molven910 and
  13. Pål R. Njølstad111
  1. 1Section for Pediatrics, Department of Clinical Medicine, University of Bergen, Bergen, Norway
  2. 2Section for Medical Genetics and Molecular Medicine, Department of Clinical Medicine, University of Bergen, Bergen, Norway
  3. 3Hormone Laboratory, Haukeland University Hospital, Bergen, Bergen, Norway
  4. 4Department of Anesthesiology, The Norwegian Radium Hospital, Oslo, Norway
  5. 5Section of Endocrinology, Akershus University Hospital, University of Oslo, Oslo, Norway
  6. 6Department of Internal Medicine, Asker and Baerum Hospital, Baerum, Norway
  7. 7Department of Internal Medicine, Trondheim University Hospital, Trondheim, Norway
  8. 8Department of Nephrology, Ullevaal University Hospital, Oslo, Norway
  9. 9Section for Pathology, The Gade Institute, University of Bergen, Bergen, Norway
  10. 10Department of Pathology, Haukeland University Hospital, Bergen, Norway
  11. 11Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
  1. Address correspondence reprint requests to Dr. Pål R. Njølstad, Section for Pediatrics, Department of Clinical Medicine, University of Bergen, N-5020 Bergen, Norway. E-mail: pal.njolstad{at}


Variants in hepatocyte nuclear factor (HNF)-4α cause maturity-onset diabetes of the young, type 1 (MODY1) and may also be risk factors for type 2 diabetes. We sequenced the HNF4A gene of 95 MODY3-negative probands from the Norwegian MODY Registry. We found three novel coding variants in exon 8 of HNF4A: G326R, T339I, and W340X. In intron 7, we noted a single nucleotide polymorphism in the binding site of a previously published primer pair, which in some cases caused allelic drop out when amplifying exon 8. We also detected two novel sequence variants of the P2 promoter region, of which P2 −192C>G showed linkage with diabetes in two families (maximal logarithm of odds score of 3.1 and 0.8, respectively). This variant and a surrounding haplotype restricted by 3.7 Mb was also found in two Danish MODY pedigrees. The age of onset was higher in the P2 −192C>G carriers (median 45 years) compared with that reported for other MODY1 individuals. We could not support a biological role of the P2 promoter variant by in vitro transfection assays. In conclusion, we have identified three novel HNF4A mutations and a 3.7-Mb haplotype, including the HNF4A P2 promoter, which was linked with diabetes.


  • L.B., S.J., and K.M. contributed equally to this article.

    Additional information for this article can be found in an online appendix at

    DOI: 10.2337/db05-1677

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted March 13, 2006.
    • Received December 23, 2005.
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