Disruption of a binding site for hepatocyte nuclear factor 1 in the protein C gene promoter is associated with hereditary thrombophilia.

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  • Additional Information
    • Source:
      Publisher: IRL Press at Oxford University Press Country of Publication: England NLM ID: 9208958 Publication Model: Print Cited Medium: Print ISSN: 0964-6906 (Print) Linking ISSN: 09646906 NLM ISO Abbreviation: Hum Mol Genet Subsets: MEDLINE
    • Publication Information:
      Original Publication: Oxford, England ; New York : IRL Press at Oxford University Press, c1992-
    • Subject Terms:
      Nuclear Proteins*; DNA-Binding Proteins/*genetics ; Liver/*metabolism ; Point Mutation/*genetics ; Promoter Regions, Genetic/*genetics ; Protein C/*genetics ; Thrombophlebitis/*genetics ; Transcription Factors/*genetics; Adult ; Base Sequence ; Binding Sites/genetics ; Female ; Gene Expression/genetics ; Hepatocyte Nuclear Factor 1 ; Hepatocyte Nuclear Factor 1-alpha ; Hepatocyte Nuclear Factor 1-beta ; Humans ; Molecular Sequence Data ; Protein C/metabolism ; Thrombophlebitis/metabolism ; Transcription Factors/metabolism
    • Abstract:
      A heterozygous T-->C transition was detected in the putative promoter region of the protein C (PROC) gene in a patient with type I protein C deficiency and a history of recurrent venous thrombosis. This mutation occurred 14 bp upstream of the transcription initiation site and within a sequence strongly homologous to the consensus binding site for the liver-enriched transcription factor, hepatocyte nuclear factor 1 (HNF-1). Transfection experiments demonstrated that a CAT reporter gene construct containing 626 bp of the putative PROC gene promoter was capable of driving CAT expression in HepG2 hepatoma cells. Levels of CAT expression from constructs bearing the mutation were found to be drastically reduced by comparison with the wild-type, consistent with the reduced plasma protein C antigen levels observed in the patient. Gel retardation and cotransfection experiments demonstrated that the mutation abolished both the binding and the transactivating ability of HNF-1 observed with the wild-type PROC gene promoter. Further, the ability of the mutation to disrupt HNF-1 binding appears to be a function not only of the nature of the nucleotide substitution and its position within the recognition sequence, but also of the relative affinity of the wild-type binding site for HNF-1. This analysis is therefore indicative of a vital role for HNF-1 in the expression of the PROC gene in vivo. Taken together with the identification of a human hepatoma cell line which contains HNF-1 but which does not express protein C, these findings are consistent with the view that HNF-1 is necessary although not sufficient for PROC gene expression in the liver.
    • Gene Symbol:
      PROC
    • Accession Number:
      0 (DNA-Binding Proteins)
      0 (HNF1A protein, human)
      0 (HNF1B protein, human)
      0 (Hepatocyte Nuclear Factor 1-alpha)
      0 (Nuclear Proteins)
      0 (Protein C)
      0 (Transcription Factors)
      126548-29-6 (Hepatocyte Nuclear Factor 1)
      138674-15-4 (Hepatocyte Nuclear Factor 1-beta)
    • Publication Date:
      Date Created: 19941201 Date Completed: 19950413 Latest Revision: 20190512
    • Publication Date:
      20231215
    • Accession Number:
      10.1093/hmg/3.12.2147
    • Accession Number:
      7881411