|
|
 Previous Article | Table of Contents | Next Article 
Blood, 1 October 2002, Vol. 100, No. 7, pp. 2515-2521
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Molecular basis of quantitative factor V deficiency
associated with factor V R2 haplotype
Tomio Yamazaki,
Gerry A. F. Nicolaes,
Kristoffer W. Sørensen, and
Björn Dahlbäck
From the Department of Laboratory Medicine, Division of
Clinical Chemistry, Lund University, Wallenberg Laboratory, University
Hospital, Malmö, Sweden; and the Cardiovascular Research
Institute Maastricht, Department of Biochemistry, Maastricht
University, The Netherlands.
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.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
D. Scanavini, D. Girelli, B. Lunghi, N. Martinelli, C. Legnani, M. Pinotti, G. Palareti, and F. Bernardi
Modulation of Factor V Levels in Plasma by Polymorphisms in the C2 Domain
Arterioscler. Thromb. Vasc. Biol.,
January 1, 2004;
24(1):
200 - 206.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. S. Singh, M. A. Bukys, D. O. Beck, and M. Kalafatis
Amino Acids Glu323, Tyr324, Glu330, and Val331 of Factor Va Heavy Chain Are Essential for Expression of Cofactor Activity
J. Biol. Chem.,
July 18, 2003;
278(30):
28335 - 28345.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
