title: Disruption of a C/EBP binding site in the factor IX promoter is associated with haemophilia B.
abstract: 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.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, UK.
authors.forename: M
authors.initials: M
authors.lastname: Crossley
authors.forename: G G
authors.initials: GG
authors.lastname: Brownlee
mesh_terms: D000367:Age Factors; D000595:Amino Acid Sequence; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D005164:Factor IX / Q000235:genetics*; D005786:Gene Expression Regulation; D002836:Hemophilia B / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D005164:Factor IX