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Factor VIII inhibitors in two families with mild haemophilia A: structural analysis of the mutations

Knobe, Karin LU ; Villoutreix, B O; Tengborn, L I; Petrini, P and Ljung, Rolf LU (2000) In Haemostasis 30(5). p.268-279
Abstract
The development of inhibitory antibodies against coagulation factor VIII (FVIII) in patients with mild haemophilia A is uncommon. We describe here two families in which three or two members have developed inhibitors, suggesting a familial predisposition. The mutations found, in the A2 (Arg593Cys) and C1 domains (Tyr2105Cys), have been reported to give rise to inhibitor development in single individuals in addition to the family cluster we describe, strongly suggesting that these amino acid substitutions give rise to a more immunogenic protein. The analysis of structural models of activated factor VIII revealed that Arg593 is solvent-exposed and involved in a network of electrostatic interactions while Tyr2105 is partially buried and has... (More)
The development of inhibitory antibodies against coagulation factor VIII (FVIII) in patients with mild haemophilia A is uncommon. We describe here two families in which three or two members have developed inhibitors, suggesting a familial predisposition. The mutations found, in the A2 (Arg593Cys) and C1 domains (Tyr2105Cys), have been reported to give rise to inhibitor development in single individuals in addition to the family cluster we describe, strongly suggesting that these amino acid substitutions give rise to a more immunogenic protein. The analysis of structural models of activated factor VIII revealed that Arg593 is solvent-exposed and involved in a network of electrostatic interactions while Tyr2105 is partially buried and has hydrophobic interactions essentially with Ile2144. All these residues are strictly conserved in the FVIII amino acid sequence from man, pig and mouse, suggesting, at least, that they have structural roles. We propose that the two mutations in these families could cause mild haemophilia A because they induce local conformational changes (and possible secretion or intermolecular interaction problems, e.g., with von Willebrand factor) compatible with immunogenicity and production of inhibitors against the infused wild-type FVIII. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Haemostasis
volume
30
issue
5
pages
268 - 279
publisher
S. Karger AG
external identifiers
  • pmid:11251334
  • scopus:0034467035
ISSN
0301-0147
DOI
10.1159/000054143
language
English
LU publication?
yes
id
4f387caf-4ee6-4f0d-8e5b-123e48f8fa3a (old id 1118259)
date added to LUP
2008-06-17 14:44:10
date last changed
2017-01-01 06:52:55
@article{4f387caf-4ee6-4f0d-8e5b-123e48f8fa3a,
  abstract     = {The development of inhibitory antibodies against coagulation factor VIII (FVIII) in patients with mild haemophilia A is uncommon. We describe here two families in which three or two members have developed inhibitors, suggesting a familial predisposition. The mutations found, in the A2 (Arg593Cys) and C1 domains (Tyr2105Cys), have been reported to give rise to inhibitor development in single individuals in addition to the family cluster we describe, strongly suggesting that these amino acid substitutions give rise to a more immunogenic protein. The analysis of structural models of activated factor VIII revealed that Arg593 is solvent-exposed and involved in a network of electrostatic interactions while Tyr2105 is partially buried and has hydrophobic interactions essentially with Ile2144. All these residues are strictly conserved in the FVIII amino acid sequence from man, pig and mouse, suggesting, at least, that they have structural roles. We propose that the two mutations in these families could cause mild haemophilia A because they induce local conformational changes (and possible secretion or intermolecular interaction problems, e.g., with von Willebrand factor) compatible with immunogenicity and production of inhibitors against the infused wild-type FVIII.},
  author       = {Knobe, Karin and Villoutreix, B O and Tengborn, L I and Petrini, P and Ljung, Rolf},
  issn         = {0301-0147},
  language     = {eng},
  number       = {5},
  pages        = {268--279},
  publisher    = {S. Karger AG},
  series       = {Haemostasis},
  title        = {Factor VIII inhibitors in two families with mild haemophilia A: structural analysis of the mutations},
  url          = {http://dx.doi.org/10.1159/000054143},
  volume       = {30},
  year         = {2000},
}