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Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 2000-2007
Two novel type 2N von Willebrand disease-causing mutations that
result in defective factor VIII binding, multimerization, and
secretion of von Willebrand factor
Simon Allen,
Adel M. Abuzenadah,
Joanna L. Blagg,
Joanna Hinks,
I. Mandy Nesbitt,
Anne
C. Goodeve,
Turkiz Gursel,
Jørgen Ingerslev,
Ian R. Peake, and
Martina E. Daly
From the Division of Molecular and Genetic Medicine, Royal
Hallamshire Hospital, University of Sheffield, United Kingdom; Medical
School of Gazi University, Ankara, Turkey; University Hospital of
Skejby, Aarhus, Denmark. Submitted March 3, 1999; accepted November 29, 1999.
Two novel mutations, a T-to-C transition at nucleotide 2612 and a
T-to-G transversion at nucleotide 3923 of the von Willebrand factor
(vWF) complementary DNA, were detected by analysis of the vWF gene in
DNA from members of 2 families with atypical von Willebrand disease.
The T2612C transition predicts substitution of cysteine by arginine at
amino acid position 788 (C788R), and the T3923G transversion predicts
substitution of cysteine by glycine at position 1225 (C1225G) of
pre-pro-vWF. The patients homozygous for the C788R and
C1225G mutations both had a partial vWF deficiency (0.18 IU/mL and 0.07 IU/mL vWF antigen, respectively); vWF in
plasma from patients homozygous for either the C788R or the C1225G
mutation failed to bind factor VIII and lacked high molecular weight
multimers. Recombinant (r) vWF molecules having the C788R or C1225G
mutation were expressed in COS-7 cells. Both rvWF C788R and rvWF C1225G exhibited significantly impaired secretion and failed to bind factor VIII. Recombinant vWF C788R in COS-7 culture medium showed a
severe reduction in high molecular weight multimers, whereas rvWF
C1225G showed a very mild reduction in high molecular weight multimers
when compared with wild-type rvWF.
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