Zheng Xing-Wu, Kudaravalli Rama, Russell Theresa T, DiMichele Donna M, Gibb Constance, Russell J Eric, Margaritis Paris, Pollak Eleanor S
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, USA.
Blood Coagul Fibrinolysis. 2011 Oct;22(7):624-7. doi: 10.1097/MBC.0b013e3283497699.
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.
青春期后双卵双胎男性中严重的凝血因子VII（FVII）缺乏症是由FVII基因中的两个点突变引起的，一个是启动子区域-60处的T→C转换，另一个是氨基酸348处的组氨酸到精氨酸的替换；这两个突变都阻止了血浆功能性FVII的持续存在。本报告记录了两名FVII缺乏症双胞胎患者从婴儿期到成年期FVII凝血活性（FVII:C）的纵向实验室测量结果；它还详细介绍了-60 T→C突变的具体生化分析。结果显示，婴儿期FVII:C水平低于1%，在青春期及成年期仍严重降低。利用肝细胞核因子4α（HNF4α）共转染和染色质免疫沉淀试验进行的体外分析表明，-60 T→C突变严重削弱了FVII启动子与转录因子HNF4α之间的功能相互作用。FVII基因与HNF4α之间的相互作用在正常FVII表达中的重要性，为编码凝血蛋白的常染色体基因的调控表达提供了一个体内例证。此处报告的FVII:C的稳定性和青春期前后患者的症状表明，与编码凝血因子IX的基因启动子区域类似突变的表达相反，FVII的表达不依赖雄激素。
