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Severe factor VII deficiency due to a mutation disrupting a hepatocyte
nuclear factor 4 binding site in the factor VII promoter
AA Arbini, ES Pollak, JK Bayleran, KA High and KA Bauer
Department of Medicine, Brockton-West Roxbury Department of Veterans
Affairs Medical Center, MA, USA.
Although small deletions, splice site abnormalities, missense, and nonsense
mutations have been identified in patients with factor VII deficiency,
there have been no reports of mutations in the factor VII promoter. We
investigated a girl with factor VII levels that were less than 1% of normal
in association with a severe bleeding diathesis. The patient is homozygous
for a T to G transversion that occurs 61 bp before the translation start
site. This nucleotide is in a sequence that is an hepatocyte nuclear factor
4 (HNF-4) binding site within the factor VII promoter (ACTTTG
AE-->ACGTTG). Using gel mobility shift assays, we show that the mutation
disrupts the binding of HNF-4 to its cognate binding site. In growth
hormone reporter gene assays, the activity of a plasmid containing the
mutant promoter was 6.7% of the wild-type promoter plasmid. Although HNF-4
was able to transactivate the wild-type factor VII promoter 5.4-fold in
HeLa cells, no transactivation could be shown with the mutant promoter.
These findings indicate that HNF-4 exerts a major positive regulatory
effect on factor VII expression and provides in vivo evidence that binding
of this transcription factor is critical for normal factor VII expression.
Volume 89,
Issue 1,
pp. 176-182,
01/01/1997
Copyright © 1997 by The American Society of Hematology
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