Homozygous C2362F von Willebrand factor induces intracellular retention of mutant von Willebrand factor resulting in autosomal recessive severe von Willebrand disease

British Journal of Haematology
P TjernbergJ C J Eikenboom

Abstract

The missense mutation of cysteine 2362 to a phenylalanine in von Willebrand factor (VWF) has been detected in several Italian families with autosomal recessive, severe von Willebrand disease. We investigated how this amino acid change in VWF may lead to a predominantly quantitative defect. This mutation was studied in vitro by transient expression of the full-length mutant VWF-C2362F protein and in vivo by analysis of plasma VWF after infusion of 1-deamino-8-d-arginine vasopressin (DDAVP) in a patient homozygous for this mutation. Single transfections of pSVHVWF-C2362F and co-transfections of mutant and wild-type constructs resulted in 8% and 50% VWF antigen, respectively, in conditioned medium. These reduced levels are in accordance with observations in homozygous and heterozygous carriers of the mutation. In addition, VWF-C2362F was retained intracellularly. Similar results were obtained for C2362F and C2362A. After infusion of DDAVP in a homozygous patient, a twofold decrease in half-life of plasma VWF-C2362F was observed. This was not explained by increased susceptibility of recombinant VWF-C2362F to ADAMTS13. It was concluded that VWF-C2362F causes reduced VWF plasma levels due to impaired secretion and intracellular reten...Continue Reading

References

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Citations

Mar 1, 2013·Thrombosis and Haemostasis·Alessandra CasonatoLuigi De Marco
Jan 15, 2013·Journal of Thrombosis and Haemostasis : JTH·M BowmanUNKNOWN Association of Hemophilia Clinic Directors of Canada
May 21, 2011·The Journal of Biological Chemistry·Jiong-Wei WangJeroen Eikenboom
Sep 19, 2019·Haemophilia : the Official Journal of the World Federation of Hemophilia·Shariq AhmedJohannes Oldenburg

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