MODY associated with two novel hepatocyte nuclear factor-1alpha loss-of-function mutations (P112L and Q466X)

Biochem Biophys Res Commun. 2000 Dec 29;279(3):792-8. doi: 10.1006/bbrc.2000.4024.


Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of diabetes characterized by early onset of pancreatic dysfunction. MODY type 3 is caused by mutations in the hepatocyte nuclear factor (HNF)-1alpha. During a screening of Norwegian patients with suspected MODY we identified two novel HNF-1alpha mutations, P112L and Q466X. The molecular mechanisms underlying the disease were studied by analyzing the DNA binding properties, transcriptional activation, and subcellular localization of HNF-1alpha P112L and Q466X compared to wild type HNF-1alpha. P112L had reduced ability to bind an HNF1 consensus sequence and to activate transcription. Q466X did not differ from wild type HNF-1alpha in DNA binding activity. Transactivation, however, was markedly reduced. When both mutants were coexpressed with wild type HNF-1alpha in HeLa cells, transcriptional activity appeared unaffected, suggesting that a dominant-negative mechanism was not present. Immunolocalization experiments showed that P112L HNF-1alpha was correctly targeted to nuclei in HeLa cells. In contrast, some Q466X HNF-1alpha protein was retained in the cytoplasm, which indicated that the mechanism for nuclear localization was disturbed. Thus, the HNF-1alpha mutations P112L and Q466X both seem to impair pancreatic beta-cell function by loss-of-function mechanisms; P112L by reduced DNA binding and reduced ability to transactivate, and Q466X by reduced transactivation and incomplete nuclear targeting.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA / metabolism
  • DNA Mutational Analysis
  • DNA-Binding Proteins*
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Glutamine / genetics
  • HeLa Cells
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 1-beta
  • Hepatocytes / metabolism
  • Humans
  • Immunohistochemistry
  • Leucine / genetics
  • Male
  • Mutagenesis, Site-Directed
  • Nuclear Proteins*
  • Pedigree
  • Proline / genetics
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcriptional Activation


  • DNA-Binding Proteins
  • HNF1A protein, human
  • HNF1B protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Nuclear Proteins
  • Transcription Factors
  • Glutamine
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-beta
  • DNA
  • Proline
  • Leucine