title: Mutation in the factor VII hepatocyte nuclear factor 4α-binding site contributes to factor VII deficiency.
abstract: Severe coagulant factor VII (FVII) deficiency in postpubertal dizygotic twin males results from two point mutations in the FVII gene, a promoter region T→C transition at -60 and a His-to-Arg substitution at amino acid 348; both mutations prevent persistence of plasma functional FVII. This report documents longitudinal laboratory measurements from infancy to adulthood of FVII coagulant activity (FVII:C) in the twin FVII-deficient patients; it also details specific biochemical analyses of the -60 T→C mutation. The results revealed FVII:C levels of less than 1% in infancy that remain severely decreased through puberty and into adulthood. In-vitro analyses utilizing hepatocyte nuclear factor 4α (HNF4α) co-transfection and a chromatin immunoprecipitation assay indicate that the -60 T→C mutation severely diminishes functional interaction between the FVII promoter and transcription factor HNF4α. The importance of interaction between the FVII gene and HNF4α in normal FVII expression provides an in-vivo illustration of the regulated expression of an autosomal gene encoding a coagulation protein. The constancy of FVII:C and peripubertal patient symptomatology reported here illustrates androgen-independent expression in contrast to expression with an analogous mutation in the promoter region of the gene encoding coagulation FIX.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, USA.
authors.forename: Xing-Wu
authors.initials: XW
authors.lastname: Zheng
authors.forename: Rama
authors.initials: R
authors.lastname: Kudaravalli
authors.forename: Theresa T
authors.initials: TT
authors.lastname: Russell
authors.forename: Donna M
authors.initials: DM
authors.lastname: DiMichele
authors.forename: Constance
authors.initials: C
authors.lastname: Gibb
authors.forename: J Eric
authors.initials: JE
authors.lastname: Russell
authors.forename: Paris
authors.initials: P
authors.lastname: Margaritis
authors.forename: Eleanor S
authors.initials: ES
authors.lastname: Pollak
mesh_terms: D000328:Adult; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005167:Factor VII / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005168:Factor VII Deficiency / Q000097:blood / Q000235:genetics*; D006367:HeLa Cells; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008137:Longitudinal Studies; D008297:Male; D010957:Plasmids; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D014162:Transfection; D014429:Twins, Dizygotic
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D005167:Factor VII