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

Area of Science:

• Genetics
• Hematology
• Molecular Biology

Background:

• Coagulant factor VII (FVII) deficiency is a rare bleeding disorder.
• Genetic mutations can lead to severe FVII deficiency, impacting hemostasis.
• Understanding the molecular basis of FVII deficiency is crucial for diagnosis and treatment.

Purpose of the Study:

• To investigate the genetic and molecular basis of severe FVII deficiency in dizygotic twin males.
• To document the longitudinal FVII coagulant activity (FVII:C) levels in affected individuals.
• To analyze the impact of a specific promoter mutation on FVII gene expression.

Main Methods:

• Longitudinal laboratory measurements of FVII:C from infancy to adulthood.
• Biochemical analyses of a T→C transition mutation at position -60 in the FVII promoter region.
• In-vitro hepatocyte nuclear factor 4α (HNF4α) co-transfection assays.
• Chromatin immunoprecipitation (ChIP) assays to assess transcription factor interaction.

Main Results:

• Patients exhibited FVII:C levels consistently below 1% from infancy through adulthood.
• The -60 T→C promoter mutation significantly reduced the interaction between the FVII promoter and HNF4α.
• In-vitro analyses confirmed the diminished functional interaction of the FVII promoter with HNF4α.

Conclusions:

• Severe FVII deficiency in these twins is caused by two point mutations, including a promoter mutation affecting HNF4α binding.
• The study illustrates the regulation of an autosomal gene encoding a coagulation protein via transcription factor interaction.
• FVII:C levels remained constant and independent of androgen influence, contrasting with other coagulation factor gene expressions.