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Blood, Vol. 91 No. 4 (February 15), 1998:
pp. 1135-1139
A Novel Mutation of Arg306 of Factor V Gene in Hong Kong Chinese
By
W.P. Chan,
C.K. Lee,
Y.L. Kwong,
C.K. Lam, and
Raymond Liang
From the Departments of Medicine and Pathology, University of Hong
Kong, Queen Mary Hospital, Hong Kong.
 |
ABSTRACT |
We have analyzed 83 unrelated Hong Kong Chinese for the presence of
genetic variants of factor V gene. Forty-three of them had a history of
deep vein thrombosis. The DNA sequence variations of exons 7, 10, and
13, where the codons for Arg306, Arg506, and Arg679 are located,
respectively, were studied by denaturing gradient gel electrophoresis.
The G1691A (Arg 506Gln) mutation in exon 10 was not detectable in
any of the 83 subjects. However, a high allelic frequency for the
G1628A (Arg 485Lys) substitution was detectable in the same exon.
We have also identified a novel DNA sequence mutation (A1090G) in
exon 7 that resulted in Arg 306Gly substitution in 2 thrombotic
patients and 1 nonthrombotic subject. Fresh blood samples were
available from one of them for analysis of activated protein C
resistance and the result was negative. Variation of DNA sequence was
not found in exon 13 in any of our 83 subjects. The results of this
study showed that, although the Arg 506Gln mutation was rarely found
in the Hong Kong Chinese population, a different mutation site such as
A 1090G in exon 7 of the factor V gene (Arg 306) may be of clinical
importance.
| |
INTRODUCTION |
HUMAN COAGULATION factor V acts as a
cofactor in the conversion of prothrombin to thrombin in the
coagulation process. In plasma, this high molecular weight glycoprotein
is converted first to its active form, factor Va, by factor Xa
and/or  -thrombin. Factor Va is then quickly inactivated by
activated protein C (APC) for maintenance of hemostasis. This mechanism
of factor Va inactivation is an ordered event.1 Factor Va
is first cleaved at Arg 506 and then at Arg 306 and Arg 679. The
peptide bond cleavage at Arg506 is essential for the subsequent optimal
exposure of cleavage sites at Arg 306 and Arg 679. Peptide bond
cleavage at Arg 306 appears to occur in a membrane-bound fashion and
only accounts for the initial 70% loss of activity. The subsequent
peptide bond cleavage at Arg 679 is responsible for the loss of
remaining activity. Therefore, any defect on one or more of these three
cleavage sites can potentially affect the APC inactivation process even
though the factor V procoagulation activity may remain normal.
It has been reported that the most common defect among patients with
deep vein thrombosis (DVT) is related to APC resistance.2-4 A molecular defect resulting in APC resistance was identified as a
single point mutation (G1691 A) in the factor V gene. It causes a single amino acid substitution (Arg 506Gln) in the
factor V molecule.5-7 This results in the loss of APC
cleavage site at Arg 506 and subsequent ineffective peptide bond
cleavage processes at Arg 306 and Arg 679. The rate of inactivation of
mutant factor Va is diminished resulting in a higher level of thrombin.
Patients with this genetic defect may develop a hypercoagulable state. It is well aware that the heterozygous state for this factor V gene
mutation is associated with a fivefold to 10-fold increase in the risk
of thrombosis and a 50- to 100-fold for the homozygous state.5,8,9 This genetic defect is found predominantly in
Caucasian populations.5,8,10,11 This mutation and APC resistance is extremely rare in Asian populations.12
The effects of protein S and factor Xa on APC-catalyzed factor Va
inactivation have also been studied. Protein S accelerates factor Va
inactivation by selectively promoting the slow cleavage at Arg 306. Factor Xa protects factor Va from inactivation by APC by selectively
blocking peptide bond cleavage at Arg 506. Inactivation of factor Va
R506Q, which was isolated from the plasma of homozygous APC-resistant
patient lacking the Arg 506 cleavage site, was stimulated by protein S
but not affected by factor Xa. This confirms that the target sites of
protein S and factor Xa involve Arg 306 and Arg 506, respectively. It
has been observed that the large difference between the rates of
APC-catalyzed inactivation of normal factor Va and factor Va R506Q were
almost completely abolished in the presence of factor Xa and protein S. This may explain why, in the absence of other risk factors, APC
resistance only results in a weak prothrombotic state.13
There is further evidence to suggest that factor V gene abnormality
responsible for the APC resistance may be not be a risk factor in the
majority of some populations, but that it is a genetic risk factor in a significant minority and that it favors the clinical expression of
protein C deficiency.14
So far, G1691A mutation is the only genetic abnormality
reported for the factor V gene resulting in APC resistance. In this study, we examined the whole exon 10 of factor V gene, in which the
coding sequence for Arg 506 was located, of Hong Kong Chinese patients
with or without DVT by denaturing gradient gel electrophoresis (DGGE)
for detection of novel gene mutation. Also, the analysis was extended
to exon 7 and 13, where Arg 306 and Arg 679 were respectively located.
| |
MATERIALS AND METHODS |
Forty-three unrelated Hong Kong Chinese patients with a definite
history of DVT and 40 nonthrombotic patients were recruited for this
study. High molecular weight DNA was extracted from peripheral blood of
these 83 subjects.
Polymerase chain reaction (PCR) and Mnl/I restrictive enzyme digest.
The entire exon 10 containing the coding sequence of Arg 506 was
amplified from genomic DNA by PCR. The two primers used were identical
to those described by Ridker et al15 (5 primer,
acccacagaaatgatgccag; 3 primer, tgcccattattagccaggag). The PCR
product was a 233-bp fragment. In a total volume of 100 µL, the PCR
reagents contained 1 µg genomic DNA, 50 pmol of each primer, 200 µmol/L of each deoxynucleoide triphosphate (Pharmacia), 1× Tag
buffer (10 mmol/L Tris-HCl, pH 8.3, 50 mmol/L KCl, 1.5 mmol/L
MgCl2, and 0.01% [wt/vol] gelatin), and 2.5 U of Tag
polymerase (Perkin Elmer, Cetus, Norwalk, CT). The
reaction was performed in a 0.6-mL microcentrifuge tube and a thermal
cycler (Perkin Elmer, Cetus). The thermal cycle profile was 94°C
for 5 minutes; 30 cycles of 94°C for 60 seconds, 50°C for 30 seconds, and 72°C for 90 seconds; followed by a final extension of
10 minutes at 72°C.
Ten microliters of PCR product was digested with 2 U of Mnl/I (New
England Biolabs) at 37°C for 16 hours. The digestion
was terminated by incubation at 65°C and the fragments were
separated on a 6% polyacrylamide gel and visualized with ethidium
bromide.
DGGE.
Sequence variations were detected by PCR and DGGE. For each segment of
the coding exons 7, 10, and 13, a set of oligonucleotides composed of
an upstream primer with an additional 40-bp G+C-rich sequence
(GC-clamp) and a 20-mer downstream primer was used for PCR
amplification. This G-C clamp allowed better resolution of the
amplified fragments and more discriminating screening for sequence
variations by DGGE.
The thermal profile consisted of 5 minutes of denaturation at 94°C
and 30 cycles of 1 minute of denaturation at 94°C, 1 minute of
annealing at 58°C for exon 7 (58°C for exon 10 and 56°C for exon 13), and 1 minute of extension at 72°C, followed by a final extension at 72°C for 5 minutes. The specificity and the size of
the amplified fragments were checked on a 6% polyacrylamide gel.
Amplified PCR products were denatured at 94°C for 10 minutes and
were allowed to reanneal at 37°C slowly over 30 minutes to form
homoduplex and heteroduplex. The reannealed PCR products were then
subjected to electrophoresis for 3 hours at 160 V, 60°C on a 6.5%
polyacrylamide gel containing a 20% to 70% denaturing gradient (100%
denaturant = 7 mol/L urea and 40% formamide in TEA buffer [40 mmol/L
Tris, 20 mmol/L sodium acetate, 1 mmol/L EDTA, pH 7.6]).
DNA sequencing.
Direct PCR DNA sequencing was performed using the same primer sets. The
amplified PCR fragment was purified from the polyacrylamide gel and
used as template for sequencing reaction using a standard DNA
sequencing kit (US Biochemical, Cleveland, OH).
The functional coagulation assay for APC resistance.
Resistance to APC was tested on platelet-poor plasma using commercial
test kit from Chromogenix (Molnsal, Sweden), following the
manufacturer's instructions. Activated partial thromboplastin time
(APTT) was performed on the plasma samples with or without added APC
and the sensitivity ration was calculated as APTT with APC/APTT without
APC (normal, >2.1).12
| |
RESULTS |
DNA samples from 43 thrombotic and 40 nonthrombotic patients were
studied for the presence of the G1691A mutation of factor V
gene by Mnl/I restriction enzyme digestion of the amplified gene. The
mutation was not detectable in any of the samples. The same samples
were also analyzed by DGGE. Abnormal patterns suggesting the presence
of a genetic abnormality at exon 10 of the factor V gene was found in
41 of the 83 (49.3%) samples being studied. The results are shown in
Fig 1. DNA sequencing of the normal
fragments showed normal DNA sequences of exon 10 that was identical to
those previously reported in the gene bank. The abnormal DNA fragments identified were found to have a GA mutation at nucleotide
1628, which resulted in a change of the peptide sequence from Arg 485 to Lys. Among the 83 subjects, 8 (9.6%) were homozygous for the 1628 G
A mutation and 33 (39.8%) were heterozygous. The frequency distribution of this mutation was similar between the 43 thrombotic (4 homozygous and 17 heterozygous) and the 40 nonthrombotic (4 homozygous
and 16 heterozygous) patients. Identical mutation has been previously
reported by Gandrille et al14 in European populations but
at a much lower frequency.
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| Fig 1.
DGGE of the amplified exon 10 of factor V gene. Lanes 1 and 3, contol with a homozygosity for G1691A mutation. Lane 2, control with a heterozygosity for G1691A mutation. Lane 8, normal
control. Lanes 9 and 11, homozygous for G1628A mutation. Lanes 4 through 7, 10, and 12, heterozygous for G1628A mutation. (Upstream
primer, GC40-TCAGG CAGGA ACAAC ACCAT; downstream primer, GGTTA CTTCA
AGGAC AAAAT.).
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|
The PCR and DGGE technique were also applied to study the exons 7 of
factor V gene, where the coding sequence of Arg306 was located.
Abnormal patterns suggesting the presence of a genetic abnormality at
exon 7 of the factor V gene were found in 3 of the 83 (3.6%) samples
being studied. There were 2 positive cases in the thrombotic group and
1 in the nonthrombotic group. The results are shown in
Fig 2. DNA sequencing of the normal
fragments showed normal DNA sequences of exon 7 of factor V gene that
were identical to those previously reported in the gene bank. DNA
sequence analysis of the abnormal amplified fragment of exon 7 from
these 3 patients showed a heterozygous A1090G mutation
(Fig 3). To confirm the mutation, a
restriction enzyme digest of the amplified exon 7 of factor V gene with
BstNI (New England Biolabs), which has a restriction site of
CC AGG, were performed. The DNA fragments were studied by
6% polyacrylamide gel electrophoresis. The undigested DNA fragment was
a 240-bp PCR product. A complete digestion of this 240-bp DNA fragment with BstNI was expected to yield two shorter fragments of 100 and 140 bp in length (Fig 4). The presence
of an A1090G mutation resulted in the loss of the cleavage
site for BstNI. A BstNI-digested sample from a normal
control on lane 1 produced the two fragments of 100 and 140 bp in
length as expected. A BstNI-digested sample from a thrombotic
patient on lane 2 yielded three DNA fragments (100, 140, and 240 bp),
confirming heterozygosity for the A1090G mutation. The
additional 240-bp fragment represented the complete undigested PCR
product, as the result of the loss of the enzyme cleavage site of
BstNI. Similar to the normal control one lane 1, a
BstNI-digested sample from another thrombotic patient on lane 3 produced two DNA fragments of 100 and 140 bp in length, confirming the
absence of A1090G mutation. Fresh blood sample was available
only from 1 of the 3 subjects with the mutation and the patient had
history of DVT. The sample was taken while the patient was not on any
anticoagulant. Functional coagulation assay for APC resistance was
performed on the sample available and the APC sensitivity ratio was
3.2, which was normal. Other tests, including antithrombin III, protein
C, protein S, and lupus anticoagulant, were also determined on the same
blood sample and were all normal.
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| Fig 2.
DGGE of the amplified exon 7 of factor V gene. Lane 1, normal control. Lanes 2 through 7, thrombotic patients. Lane 2 shows the heteroduplexes as the result of a heterozygous A1090G
mutation. (Upstream primer, [GC-40]-TGTCC TAACT CAGCT GGGAT;
downstream primer, gtatg aaccc caaca actca.)
|
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View larger version (33K):
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| Fig 3.
DNA sequence analysis of an abnormal amplified fragment
of exon 7 of factor V gene. A heterozygous A1090G mutation was
identified.
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| Fig 4.
Polyacrylamide gel electrophoresis following the
BstNI restriction enzyme digest of a 240-bp DNA fragment of
exon 7 of factor V gene. Lane M, molecular weight marker. Lane 1, BstNI-digested sample from a normal control showing the two DNA
fragments, 100 and 140 bp. Lane 2, BstNI-digested sample from a
thrombotic patient heterozygous for A1090G mutation. It shows
three DNA fragments: 100, 140, and 240 bp. Lane 3, BstNI-digested sample from a thrombotic patient without the
A1090G mutation. Similar to lane 1, it shows only 2 DNA fragments,
100 and 140 bp. (Upstream primer, [GC-40]-TGTCC TAACT CAGCT GGGAT;
downstream primer, gtatg aaccc caaca actca.)
|
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The PCR and DGGE analysis was finally used to study exon 13 of the
factor V gene. It is the location of the codon of Arg 679. No
abnormality was found in the samples from all 83 subjects being studied.
| |
DISCUSSION |
Factor V Leiden (Arg 506Gln mutation) is known to be an
important risk factor for venous thrombo-embolism. Its prevalence is
known to vary widely among different populations. The mutation in
heterozygous or homozygous state is relatively more common in some
European populations. The allele frequency in European is estimated to
be 4.4%, with the highest prevalence among Greeks (7%). However, it
was only 0.6% in Asia Minor and the mutation was not found in Africa
and Southeast Asia.11,12,16 This may partly explain the
rarity of thrombo-embolic diseases in these populations, although other
factors may also contribute. A previous study has demonstrated the lack
of APC resistance and Arg 506Gln mutation in healthy Hong
Kong Chinese blood donors.12 None of our 43 thrombotic and
40 nonthrombotic Hong Kong patients in this study had the factor V
Leiden mutation. Our result supports the findings of previous
studies.12
An Arg 485Lys mutation at exon 10 of the factor V gene was
first described by Gandrille et al.14 They have found this
sequence variation in 3 of 104 (2.9%) normal subjects and 7 of 113 (6.4%) patients with protein C deficiency. This mutation was not
associated APC resistance in their healthy subjects and its allelic
frequency in their protein C-deficient patients was not significantly
different form that observed in healthy subjects. The Arg 485 to Lys
substitution is apparently a neutral polymorphism in terms of
procoagulant activity or susceptibility to APC. In this study, nearly
half of our 83 subjects, including both thrombotic and nonthrombotic patients, were found to have this sequence variation, suggesting a much
higher allelic frequency of this mutation in Hong Kong Chinese. Like
many other polymorphism, this Arg 485 to Lys substitution appears to
have a highly variable allelic frequency in different ethnic
populations. This mutation was seen at similar frequency in our
thrombotic and nonthrombotic subjects, supporting the hypothesis of a
neutral polymorphism in terms of procoagulant activity as originally
proposed by Gandille et al.14
We have detected in this study a previously unreported mutation
(A1090G) of the factor V gene at exon 7. This mutation
results in a Arg 306 to Gly substitution. Among our 84 subjects, 2 thrombotic patients and 1 nonthrombotic patient were found to possess
this mutation in heterozygous state. This A1090G mutation in
the codon AGG of Arg306 is a missense point mutation predicting a
replacement of arginine by a glycine residue.17 The
substitution may potentially affect APC cleavage at the Arg 306 site of
the factor V molecule. As the inactivation of factor Va is a sequential
event, initial peptide bond cleavage of residue Arg 506 results in the
exposure of other cleavage sites. The subsequent cleavage of at
residues Arg 306 and Arg 679 completes the factor Va inactivation
process. With a normal Arg 506 in these subjects, the effect of a
defect at Arg 306 is uncertain. Nevertheless, cleavage of Arg306 is
required for complete inactivation of the factor Va molecule. An Arg
306 defect may result in a protein that is cleaved at Arg506 and Arg679 only but still possesses about 60% cofactor
activity.14-18 Fresh plasma samples are only
available from 1 of the 3 subjects with the mutation. The patient had
history of DVT and the APC resistance assay on the sample was within
normal limits. At this stage, the clinical significance of the
substitution at Arg306 is not certain as the number of positive cases
in our series is small and the defect is found in both thrombotic and
nonthrombotic subjects. It is not yet possible to assess the thrombotic
risk of subjects with this defect. Large-scale epidemiologic studies on
this Arg306 mutation are warranted. The true allelic frequency
distribution of this defect in Chinese and other populations remains to
be determined. Further functional and clinical correlation is also required.
| |
FOOTNOTES |
Submitted July 7, 1997;
accepted November 10, 1997.
Supported by a Conference and Research Grant (CRCG) of the University
Research Committee of the University of Hong Kong.
Address reprint requests to Raymond Liang, MD, Department of Medicine,
Queen Mary Hospital, Hong Kong.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
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E. Norstrom, E. Thorelli, and B. Dahlback
Functional characterization of recombinant FV Hong Kong and FV Cambridge
Blood,
June 28, 2002;
100(2):
524 - 530.
[Abstract]
[Full Text]
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G. A.F. Nicolaes and B. Dahlback
Factor V and Thrombotic Disease: Description of a Janus-Faced Protein
Arterioscler. Thromb. Vasc. Biol.,
April 1, 2002;
22(4):
530 - 538.
[Abstract]
[Full Text]
[PDF]
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D. A. Lane and P. J. Grant
Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease
Blood,
March 1, 2000;
95(5):
1517 - 1532.
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F. Rodeghiero and A. Tosetto
Activated Protein C Resistance and Factor V Leiden Mutation Are Independent Risk Factors for Venous Thromboembolism
Ann Intern Med,
April 20, 1999;
130(8):
643 - 650.
[Abstract]
[Full Text]
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M. C.H. de Visser, F. R. Rosendaal, and R. M. Bertina
A Reduced Sensitivity for Activated Protein C in the Absence of Factor V Leiden Increases the Risk of Venous Thrombosis
Blood,
February 15, 1999;
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[Abstract]
[Full Text]
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Abstract
Introduction
Abstract
