Mutation in the factor VII hepatocyte nuclear factor 4 alpha-binding site contributes to factor VII deficiency

作者：Zheng Xing Wu; Kudaravalli Rama; Russell Theresa T; DiMichele Donna M; Gibb Constance; Russell J Eric; Margaritis Paris; Pollak Eleanor S^*

来源：Blood Coagulation & Fibrinolysis, 2011, 22(7): 624-627.

DOI：10.1097/MBC.0b013e3283497699

• chromatin immunoprecipitation
• factor VII deficiency
• hemophilia B Leyden
• hepatocyte nuclear factor 4

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 4 alpha (HNF4 alpha) 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 HNF4 alpha. The importance of interaction between the FVII gene and HNF4 alpha 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.

• 出版日期2011-10