Severe Factor VII Deficiency Due to a Mutation Disrupting an Sp1 Binding Site in the Factor VII Promoter

Author:

Carew Josephine A.1,Pollak Eleanor S.1,High Katherine A.1,Bauer Kenneth A.1

Affiliation:

1. From the Hematology-Oncology Section, Department of Medicine, Brockton-West Roxbury Department of Veterans Affairs Medical Center, and Harvard Medical School, Boston, MA; and the Departments of Pediatrics and Pathology and Laboratory Medicine, University of Pennsylvania and The Children’s Hospital of Philadelphia, PA.

Abstract

AbstractWe have identified a point mutation in the promoter of the factor VII gene responsible for a severe bleeding disorder in a patient from a large French-Canadian family with known consanguinity. The proband has an extremely low plasma level of factor VII antigen and factor VII coagulant activity (<1 percent of normal) and suffers from hemarthroses and chronic arthropathy. Sequencing of the patient’s factor VII 5′ flanking region, intron/exon junctions, and coding regions showed a homozygous point mutation, a C to G transversion at position −94 relative to the translation start site. We show here that this mutation prevented binding of transcription factor Sp1 and of other nuclear proteins to this region of the factor VII promoter and resulted in a 20-fold reduction in reporter gene expression in HepG2 cells. These data underscore the importance of this region of the factor VII promoter for in vivo expression of the factor VII gene.© 1998 by The American Society of Hematology.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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