title: MODY associated with two novel hepatocyte nuclear factor-1alpha loss-of-function mutations (P112L and Q466X).
abstract: 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.
authors.affiliation: Center for Medical Genetics and Molecular Medicine, University of Bergen, Bergen, N-5021, Norway.
authors.forename: L
authors.initials: L
authors.lastname: Bjørkhaug
authors.forename: H
authors.initials: H
authors.lastname: Ye
authors.forename: Y
authors.initials: Y
authors.lastname: Horikawa
authors.forename: O
authors.initials: O
authors.lastname: Søvik
authors.forename: A
authors.initials: A
authors.lastname: Molven
authors.forename: P R
authors.initials: PR
authors.lastname: Njølstad
mesh_terms: D004247:DNA / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005973:Glutamine / Q000235:genetics; D006367:HeLa Cells; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007930:Leucine / Q000235:genetics; D008297:Male; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins; D010375:Pedigree; D011392:Proline / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D005973:Glutamine; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D004247:DNA; D011392:Proline; D007930:Leucine