Disruption of a C/EBP binding site in the factor IX promoter is associated with haemophilia B

Nature. 1990 May 31;345(6274):444-6. doi: 10.1038/345444a0.


Haemophilia B (or Christmas disease) is an inherited, X-linked bleeding disorder caused by mutations in the gene for clotting factor IX. There is a rare class of patients, exemplified by haemophilia B Leyden, who suffer from haemophilia B as children but improve after puberty. In these patients, plasma factor IX concentrations are less than 10% of normal during childhood, but after puberty they gradually rise to between 40 and 80% of normal. Mutations clustered around the main transcription start point (defined as +1 (ref.2)) have been reported in seven of these patients (at -20 (refs 1, 3, 4); -6 (refs 5, 6) and +13 (refs 7, 8)). To determine how these mutations interfere with factor IX expression, we have assayed for transcription factors binding to this area and have identified a nuclear factor-1 liver (NF1-L) binding site (-99 to -76) and a binding site for the CCAAT/enhancer binding protein (C/EBP) (+1 to +18). We show that the A----G mutation at +13 prevents the binding of C/EBP to this site. Furthermore, we show that C/EBP is capable of transactivating a cotransfected normal factor IX promoter but not the mutant promoter. This is the first natural mutation to be reported which disrupts a C/EBP binding site and is an illustration of the importance of this transcription factor in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Amino Acid Sequence
  • Base Sequence
  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins / metabolism
  • Factor IX / genetics*
  • Gene Expression Regulation
  • Hemophilia B / genetics*
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation
  • Nuclear Proteins / metabolism*
  • Promoter Regions, Genetic*
  • Transcription Factors / metabolism*


  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Transcription Factors
  • Factor IX