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Molecular basis of quantitative factor V deficiency associated with factor V R2 haplotype.

Yamazaki, Tomio LU ; Nicolaes, Gerry A F; Sørensen, Kristoffer LU and Dahlbäck, Björn LU (2002) In Blood 100(7). p.2515-2521
Abstract
To investigate the molecular mechanisms of the quantitative factor V (FV) deficiency associated with the FV R2 haplotype, 4 missense mutations, Met385Thr, His1299Arg, Met1736Val, and Asp2194Gly, identified in the R2 haplotype allele, were analyzed by in vitro expression studies. The FV variant carrying all 4 mutations showed a markedly lower steady-state expression level than wild-type FV because of low synthesis rate and impaired secretion of the mutant protein. The Asp2194Gly mutation was found to play a key role in the impaired secretion of the mutant FV by interfering with its transport from the endoplasmic reticulum to the Golgi complex. The deleterious effect of the Asp2194Gly mutation was shown to be dominant among the 4 mutations.... (More)
To investigate the molecular mechanisms of the quantitative factor V (FV) deficiency associated with the FV R2 haplotype, 4 missense mutations, Met385Thr, His1299Arg, Met1736Val, and Asp2194Gly, identified in the R2 haplotype allele, were analyzed by in vitro expression studies. The FV variant carrying all 4 mutations showed a markedly lower steady-state expression level than wild-type FV because of low synthesis rate and impaired secretion of the mutant protein. The Asp2194Gly mutation was found to play a key role in the impaired secretion of the mutant FV by interfering with its transport from the endoplasmic reticulum to the Golgi complex. The deleterious effect of the Asp2194Gly mutation was shown to be dominant among the 4 mutations. The Met385Thr mutation and His1299Arg mutation had no effect on steady-state expression levels, but the secretion rates of the mutant proteins were moderately decreased by these mutations. The His1299Arg mutation partially impaired glycosylation in the C-terminal part of the B-domain of the mutant FV, which was supposed to affect the secretion rate, but not the steady-state expression level. It was also suggested that the Met385Thr mutation partially impairs posttranslational modification of the mutant FV without affecting the steady-state expression level. No deleterious effect of the Met1736Val mutation was observed in terms of expression and intracellular processing. Our in vitro data strongly suggest that the naturally existing R2 haplotype mutant FV, which carries all 4 mutations, has the potential to result in quantitative FV deficiency in vivo owing to impaired expression of the mutant protein when the Asp2194Gly mutation is present. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
100
issue
7
pages
2515 - 2521
publisher
American Society of Hematology
external identifiers
  • wos:000178266000031
  • pmid:12239164
  • scopus:0036786338
ISSN
1528-0020
DOI
10.1182/blood.V100.7.2515
language
English
LU publication?
yes
id
5b40413d-5483-4c9d-aaf8-29123ebf539f (old id 110257)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12239164&dopt=Abstract
date added to LUP
2007-07-27 14:05:11
date last changed
2017-01-01 04:38:06
@article{5b40413d-5483-4c9d-aaf8-29123ebf539f,
  abstract     = {To investigate the molecular mechanisms of the quantitative factor V (FV) deficiency associated with the FV R2 haplotype, 4 missense mutations, Met385Thr, His1299Arg, Met1736Val, and Asp2194Gly, identified in the R2 haplotype allele, were analyzed by in vitro expression studies. The FV variant carrying all 4 mutations showed a markedly lower steady-state expression level than wild-type FV because of low synthesis rate and impaired secretion of the mutant protein. The Asp2194Gly mutation was found to play a key role in the impaired secretion of the mutant FV by interfering with its transport from the endoplasmic reticulum to the Golgi complex. The deleterious effect of the Asp2194Gly mutation was shown to be dominant among the 4 mutations. The Met385Thr mutation and His1299Arg mutation had no effect on steady-state expression levels, but the secretion rates of the mutant proteins were moderately decreased by these mutations. The His1299Arg mutation partially impaired glycosylation in the C-terminal part of the B-domain of the mutant FV, which was supposed to affect the secretion rate, but not the steady-state expression level. It was also suggested that the Met385Thr mutation partially impairs posttranslational modification of the mutant FV without affecting the steady-state expression level. No deleterious effect of the Met1736Val mutation was observed in terms of expression and intracellular processing. Our in vitro data strongly suggest that the naturally existing R2 haplotype mutant FV, which carries all 4 mutations, has the potential to result in quantitative FV deficiency in vivo owing to impaired expression of the mutant protein when the Asp2194Gly mutation is present.},
  author       = {Yamazaki, Tomio and Nicolaes, Gerry A F and Sørensen, Kristoffer and Dahlbäck, Björn},
  issn         = {1528-0020},
  language     = {eng},
  number       = {7},
  pages        = {2515--2521},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Molecular basis of quantitative factor V deficiency associated with factor V R2 haplotype.},
  url          = {http://dx.doi.org/10.1182/blood.V100.7.2515},
  volume       = {100},
  year         = {2002},
}