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N1421K mutation in the glycoprotein Ib binding domain impairs ristocetin- and botrocetin-mediated binding of von Willebrand factor to platelets.

Lanke, Elsa LU ; Kristoffersson, Ann-Charlotte LU ; Isaksson, Christina LU ; Holmberg, Lars LU and Lethagen, Stefan LU (2008) In European Journal of Haematology 81. p.384-390
Abstract
von Willebrand disease (VWD) is a common inheritable bleeding disorder caused by deficiency of von Willebrand Factor (VWF), which is involved in platelet adhesion and aggregation. We report a family consisting of three patients with VWD characterized by an apparently normal multimeric pattern, moderately decreased plasma factor VIII (FVIII) and VWF levels, and disproportionately low plasma VWF:RCo levels. The patients were found to be heterozygous for the novel N1421K mutation, caused by a 4263C>G transversion in exon 28 of the VWF gene coding for the A1 domain. Botrocetin- and ristocetin-mediated binding of plasma VWF to GPIb were reduced in the patients. In vitro mutagenesis and expression in COS-7 cells confirmed the impairment of... (More)
von Willebrand disease (VWD) is a common inheritable bleeding disorder caused by deficiency of von Willebrand Factor (VWF), which is involved in platelet adhesion and aggregation. We report a family consisting of three patients with VWD characterized by an apparently normal multimeric pattern, moderately decreased plasma factor VIII (FVIII) and VWF levels, and disproportionately low plasma VWF:RCo levels. The patients were found to be heterozygous for the novel N1421K mutation, caused by a 4263C>G transversion in exon 28 of the VWF gene coding for the A1 domain. Botrocetin- and ristocetin-mediated binding of plasma VWF to GPIb were reduced in the patients. In vitro mutagenesis and expression in COS-7 cells confirmed the impairment of the mutant in botrocetin- and ristocetin-mediated VWF binding to GPIb. VWF collagen binding capacity was unaffected in plasma from the heterozygous individuals as well as in medium from transfected COS-7 cells. Our findings indicate that the N1421K substitution in the VWF affects the GPIb binding site or a recognition element by a conformational change of the A1 domain. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
European Journal of Haematology
volume
81
pages
384 - 390
publisher
Wiley-Blackwell
external identifiers
  • wos:000260185700007
  • pmid:18637125
  • scopus:54249097491
ISSN
1600-0609
DOI
10.1111/j.1600-0609.2008.01123.x
language
English
LU publication?
yes
id
8611d54a-c8fc-4721-863c-d21c7132f96e (old id 1181031)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18637125?dopt=Abstract
date added to LUP
2008-08-11 11:46:07
date last changed
2017-03-12 04:19:51
@article{8611d54a-c8fc-4721-863c-d21c7132f96e,
  abstract     = {von Willebrand disease (VWD) is a common inheritable bleeding disorder caused by deficiency of von Willebrand Factor (VWF), which is involved in platelet adhesion and aggregation. We report a family consisting of three patients with VWD characterized by an apparently normal multimeric pattern, moderately decreased plasma factor VIII (FVIII) and VWF levels, and disproportionately low plasma VWF:RCo levels. The patients were found to be heterozygous for the novel N1421K mutation, caused by a 4263C>G transversion in exon 28 of the VWF gene coding for the A1 domain. Botrocetin- and ristocetin-mediated binding of plasma VWF to GPIb were reduced in the patients. In vitro mutagenesis and expression in COS-7 cells confirmed the impairment of the mutant in botrocetin- and ristocetin-mediated VWF binding to GPIb. VWF collagen binding capacity was unaffected in plasma from the heterozygous individuals as well as in medium from transfected COS-7 cells. Our findings indicate that the N1421K substitution in the VWF affects the GPIb binding site or a recognition element by a conformational change of the A1 domain.},
  author       = {Lanke, Elsa and Kristoffersson, Ann-Charlotte and Isaksson, Christina and Holmberg, Lars and Lethagen, Stefan},
  issn         = {1600-0609},
  language     = {eng},
  pages        = {384--390},
  publisher    = {Wiley-Blackwell},
  series       = {European Journal of Haematology},
  title        = {N1421K mutation in the glycoprotein Ib binding domain impairs ristocetin- and botrocetin-mediated binding of von Willebrand factor to platelets.},
  url          = {http://dx.doi.org/10.1111/j.1600-0609.2008.01123.x},
  volume       = {81},
  year         = {2008},
}