Homozygous C2362F von Willebrand factor induces intracellular retention of mutant von Willebrand factor resulting in autosomal recessive severe von Willebrand disease
| Autor: | Giancarlo Castaman, Jeroen Eikenboom, Rogier M. Bertina, H. L. Vos, P. Tjernberg |
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| Rok vydání: | 2006 |
| Předmět: |
Heterozygote
congenital hereditary and neonatal diseases and abnormalities Vasopressin medicine.medical_specialty Mutant Mutation Missense ADAMTS13 Protein Genes Recessive medicine.disease_cause Hemostatics Von Willebrand factor hemic and lymphatic diseases Internal medicine von Willebrand Factor medicine Von Willebrand disease Coagulopathy Humans Missense mutation Deamino Arginine Vasopressin Mutation Factor VIII biology Chemistry Homozygote Hematology medicine.disease ADAMTS13 ADAM Proteins von Willebrand Diseases Endocrinology cardiovascular system biology.protein Half-Life circulatory and respiratory physiology |
| Zdroj: | British Journal of Haematology. 133:409-418 |
| ISSN: | 1365-2141 0007-1048 |
| DOI: | 10.1111/j.1365-2141.2006.06055.x |
| Popis: | Summary 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 cotransfections 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 retention. Furthermore, it is the loss of cysteine 2362 rather than the introduction of the bulky amino acid side chain that causes these effects. |
| Databáze: | OpenAIRE |
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