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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
; ; ; and
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
  • pmid:18637125
ISSN
1600-0609
DOI
10.1111/j.1600-0609.2008.01123.x
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Emergency medicine/Medicine/Surgery (013240200), Clinical Coagulation Research Unit (013242510), Neurobiology (013212024), Paediatrics (Lund) (013002000)
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
2016-04-04 08:54:39
date last changed
2022-01-29 07:34:18
@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}},
  doi          = {{10.1111/j.1600-0609.2008.01123.x}},
  volume       = {{81}},
  year         = {{2008}},
}