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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 560-568
A novel von Willebrand disease-causing mutation (Arg273Trp)
in the von Willebrand factor propeptide that results in defective
multimerization and secretion
Simon Allen,
Adel M. Abuzenadah,
Joanna Hinks,
Joanna L. Blagg,
Turkiz Gursel,
Jørgen Ingerslev,
Anne C. Goodeve,
Ian R. Peake, and
Martina E. Daly
From the Division of Molecular and Genetic Medicine, Royal
Hallamshire Hospital, University of Sheffield, UK; the Medical School
of Gazi University, Ankara, Turkey; and the University Hospital of
Skejby, Aarhus, Denmark.
In this report we describe the molecular defect underlying partial
and severe quantitative von Willebrand factor (VWF) deficiencies in 3 families previously diagnosed with types 1 and 3 Von
Willebrand-disease. Analysis of the VWF gene in affected family members
revealed a novel C to T transition at nucleotide 1067 of the VWF
complemetary DNA (cDNA), predicting substitution of arginine by
tryptophan at amino acid position 273 (R273W) of pre-pro-VWF. Two
patients, homozygous for the R273W mutation, had a partial VWF
deficiency (VWF:Ag levels of 0.06 IU/mL and 0.09 IU/mL) and lacked
high-molecular weight VWF multimers in plasma. A third patient, also
homozygous for the R273W mutation, had a severe VWF deficiency (VWF:Ag
level of less than 0.01 IU/mL) and undetectable VWF multimers in
plasma. Recombinant VWF having the R273W mutation was expressed in
COS-7 cells. Pulse-chase experiments showed that secretion of rVWFR273W was severely impaired compared with wild-type rVWF. However, the mutation did not affect the ability of VWF to form dimers in the endoplasmic reticulum (ER). Multimer analysis showed that rVWFR273W failed to form high-molecular-weight multimers present in wild-type rVWF. We concluded that the R273W mutation is responsible for the
quantitative VWF deficiencies and aberrant multimer patterns observed
in the affected family members. To identify factors that may function
in the intracellular retention of rVWFR273W, we investigated the
interactions of VWF expressed in COS-7 cells with molecular chaperones
of the ER. The R273W mutation did not affect the ability of VWF to bind
to BiP, Grp94, ERp72, calnexin, and calreticulin in COS-7 cells.
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