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Hemophilia B Leyden: substitution of thymine for guanine at position - 21
results in a disruption of a hepatocyte nuclear factor 4 binding site in
the factor IX promoter
MJ Reijnen, K Peerlinck, D Maasdam, RM Bertina and PH Reitsma
Department of Hematology, University Hospital, Leiden, The Netherlands.
Hemophilia B Leyden is an X chromosome-linked bleeding disorder
characterized by an altered developmental expression of blood coagulation
factor IX. This form of hemophilia B has been found to be associated with a
variety of single point mutations in the factor IX promoter region. We now
describe a novel point mutation, T-->G at position -21, in two related
patients with the hemophilia B Leyden phenotype. This mutation lies within
the factor IX promoter region (-40 to -9) that contains overlapping binding
sites for hepatocyte nuclear factor 4 (HNF-4) and androgen receptor.
Transient transfection assays in HepG2 cells show that the -21 mutation
causes a significant reduction in factor IX promoter activity. Gel mobility
shift assays and transient cotransfection experiments revealed that the
HNF-4-binding site but not the androgen-responsive element is disrupted by
the -21 mutation. A comparison of the -21 mutation with the previously
described -20 T-->A mutation (associated with the hemophilia B Leyden
phenotype) and -26 G-->C mutation (associated with severe hemophilia B
throughout life) was made. It shows that the -21 mutation reduced HNF-4
binding and transactivation to a similar level as the -20 mutation, whereas
the -26 mutation completely abolished HNF-4 binding and transactivation.
Mobility shift experiments indicate that there was no significant
difference in binding affinity of recombinant androgen receptor protein for
oligonucleotides containing wild-type and -21 or - 20 mutated DNA. The
binding affinity for the oligonucleotide containing the -26 mutation was
twofold lower. The results indicate that the disruption of the
HNF-4-binding site by the -21 T-->G mutation is the cause of the
bleeding disorder in these two patients. This study adds further support
for the notion that the recovery from hemophilia at puberty may not only be
related to an intact androgen-responsive element but also to the degree of
disruption of the HNF-4-binding site.
Volume 82,
Issue 1,
pp. 151-158,
07/01/1993
Copyright © 1993 by The American Society of Hematology
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