Two novel mutations in the human coagulation factor VII promoter

Anita Kavlie; Leena Hiltunen; Vesa Rasi; Hans Prydz

doi:10.1160/TH02-09-0050

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 90(02): 194-205
DOI: 10.1160/TH02-09-0050

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Two novel mutations in the human coagulation factor VII promoter

Anita Kavlie

,

Leena Hiltunen

¹Finnish Red Cross Transfusion Service, Department of Haemostasis, Helsinki, Finland

,

Vesa Rasi

¹Finnish Red Cross Transfusion Service, Department of Haemostasis, Helsinki, Finland

,

Hans Prydz

› Author Affiliations

Abstract

Summary

The factor VII genes of five unrelated Finnish female patients, F1-F5, with moderate bleeding tendency, were screened for mutations using single strand conformational polymorphisms and DNA sequencing. Heterozygous shifts were detected in exons 5 and 8 for patient F1, and sequencing confirmed the presence of the silent dimorphism H115H, the polymorphism R353Q and the mutation A294V. The patient F1 was also heterozygous for a novel –59T/G transversion mutation in the Hepatocyte nuclear factor 4-binding site. The remaining four patients carried a –32A/C transversion mutation located in a footprint (–51 to –32) covering the major transcription initiation start site (–51). There was also a consensus sequence match to an initiator response-like binding element covering –51. Two patients were homozygous and two heterozygous for this mutation. Plasma FVII:Ag and FVII:C levels were reduced in parallel. A strong reduction in binding affinity of a specific nuclear protein to the –32C-containing oligonucleotide was found by electrophoretic mobility shift assays on nuclear extracts from HepG2 cells. EDTA caused no reduced binding. A minimal promoter (–191 to +15) containing the wild-type sequence or the –32A/C or –59T/G mutations was cloned in front of the firefly luciferase reporter gene and transiently transfected into Hep3B cells. Reduced activities [23.0 ± 3.1% (–32C), 55.4 ± 6.3% (–59G), 100% (wild-type construct)] were found for the mutated promoters. Southwestern blotting and UV crosslinking analysis showed binding of three proteins (20, 20 and 50 kDa) to the putative initiator response element. The –32A/C mutant oligonucleotide bound two proteins.

Keywords

HNF4 - Initiator response element - mutations

Full Text

References

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