|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 2010-2014
A Common Genetic Polymorphism (46 C to T Substitution) in the
5 -Untranslated Region of the Coagulation Factor XII Gene Is
Associated With Low Translation Efficiency and Decrease in Plasma
Factor XII Level
By
Taisuke Kanaji,
Takashi Okamura,
Koichi Osaki,
Mika Kuroiwa,
Kazuya Shimoda,
Naotaka Hamasaki, and
Yoshiyuki Niho
From the First Department of Internal Medicine, Faculty of Medicine,
Kyushu University, Fukuoka, Japan; the Department of Clinical Chemistry
and Laboratory Medicine, Faculty of Medicine, Kyushu University,
Fukuoka, Japan.
 |
ABSTRACT |
We studied the Hga I polymorphism (46 C/T) in the
5 -untranslated region of the coagulation factor XII (FXII) gene
corresponding to four bases upstream from the ATG translation
initiation codon. By using allele-specific restriction analysis with
restriction endonuclease Hga I, the allele frequency of 46C/T was
estimated to be 0.27/0.73 in Orientals (allele number =152), and
conversely, 0.8/0.2 in Caucasians (allele number =40). Because it has
been reported that plasma levels of FXII were lower in Orientals than in Caucasians, we investigated the relationship between this
polymorphism and plasma levels of FXII. As a result, there were
significant differences in plasma FXII levels between these three
allele types: C/C,170±38% (178±27%); C/T, 141±29%
(123±34%); and T/T, 82±19% (61±11%) [FXII activity (FXII
antigen levels)]. In heterozygotes of 46 C/T both alleles were equally
transcribed in hepatocytes, as determined by reverse transcription
polymerase chain reaction (RT-PCR), suggesting little influence of the
polymorphism at the level of transcription or on the stability of mRNA.
In in vitro transcription/translation analysis, less FXII was produced
from cDNA containing 46 T than from that containing 46 C. Therefore, it
is highly likely that the 46 T polymorphism in the FXII gene decreased
the translation efficiency and led to low plasma levels of FXII
activity and antigen, probably due to the creation of another ATG codon
and/or impairment of the consensus sequence for the translation
initiation scanning model.
| |
INTRODUCTION |
PLASMA COAGULATION factor XII (FXII) is a
serine protease precursor that is primarily produced and secreted by
hepatocytes and is involved in the initiation of the intrinsic
coagulation pathway, in fibrinolysis, in the generation of bradykinin,
and in the complement system.1 FXII is composed of COOH
terminal catalytic domain, two fibronectin-type domains, an epidermal
growth factor domain, and a kringle domain that is a component found in
most proteins involved in the fibrinolysis system.2 Several patients with inherited FXII deficiency were identified mainly through
findings of prolonged activated partial thromboplastin time (APTT)
before surgery.3,4 However, these patients did not show the
bleeding tendency. Rather, they have been reported to have
thromboembolic predisposition.5,6
cDNA7-10 and gene structure11 of the human FXII
have been elucidated. The gene spans a total of 12kb and is composed of 14 exons.11 The gene is reported to be located
at 5q33-qter in the human chromosome.12 cDNA of FXII is
2044 bp in length and is composed of 49 bases of 5-untranslated,
1845 bases of amino acid coding, and 150 bases of 3-noncoding
sequences. The transcription was initiated at 49 bases upstream from
the translation initiation ATG codon, as determined by the methods of
S1 nuclease mapping and primer extension.11
The plasma levels of FXII have been determined to be approximately 30 µg/mL (range: 15 to 47 µg/mL).13 No differences with sex in respect to adult ages have been reported.4,14
However, the concentration of plasma FXII has been known to have wide
variation between individuals and races.14 Gordon et
al15 documented that levels of plasma XII in Orientals were
approximately only half of that in Caucasians. However, the reason
remains undetermined to date.
Nucleotide sequencing analysis of a Japanese family with congenital
FXII deficiency showed 126 Arg to Pro substitution as a responsible
mutation for the deficiency.16 On that occasion an
unidentified nucleotide polymorphism, the substitution from 46 cytosine
to thymidine in exon 1 of the FXII gene, was unexpectedly found. This
nucleotide polymorphism is localized at the 5-untranslated region and is close to the translation initiation ATG codon (4 bases
upstream). Hence, it is suspected that this substitution affects the
translation efficiency. We report here that a high prevalence of 46 C
to T substitution was found in Orientals and led to reduced levels of
plasma FXII through low translation efficiency in hepatocytes.
| |
MATERIALS AND METHODS |
Subjects.
Blood donors were 76 Orientals (Japanese) and 20 Caucasians. Liver
specimens were obtained from patients with hepatic disorders who were
undergoing liver biopsy or resection, after informed consent was
obtained.
Blood collection and laboratory analysis.
Blood was collected in tubes containing 0.1 volumes of 0.106 mmol/L
trisodium citrate. Plasma was prepared by centrifugation for 10 minutes
at 2,000g at room temperature and then stored at  70°C in 1.5 mL aliquots.
FXII activity was measured by the APTT method by using a synthetic
substrate specific for thrombin (Tos-Gly-Pro-Arg-ANBA-isopropylamide) and FXII-deficient plasma.17 FXII antigen was measured by
Laurell's method by using rabbit polyclonal antibody against human
FXII.18 Blood for the FXII assays was obtained from healthy
adult volunteers (31 Japanese and 20 Caucasians) with age ranges from
15 to 69 years (means 33±12 years). Pooled plasma from 100 healthy
Japanese subjects was used as a standard plasma (100% in activity and
antigen).
Isolation of DNA and RNA, and polymerase chain reaction (PCR).
Genomic DNA was isolated from peripheral blood leukocytes by standard
procedures.19 Exon 1 of the FXII gene was amplified by PCR
by using the primers shown in Fig 1. Total
RNA from liver was isolated with an RNA isolation kit (Isogen, Nippon
gene, Tokyo, Japan). Ten µg of total RNA was used to synthesize cDNA
by using a random hexamer and cDNA synthesis kit (Takara RNA PCR Kit,
Takara Shuzo Co, Ltd, Otsu, Japan). Nine µL of this solution was used as a template for PCR. Figure 1 shows the locations and sequences of
oligonucleotide primer pairs used in this study. To analyze the
polymorphism, PCR products were digested by Hga I (New England BioLabs,
Beverly, MA) at 37°C for 3 hours, subjected to 2% agarose gel or
5% polyacrylamide gel electrophoresis, and stained by ethidium bromide
(allele-specific restriction analysis).
View larger version (21K):
[in this window]
[in a new window]
| Fig 1.
Schematic illustration of the factor XII gene and the
locations and sequences of PCR primers. Arrows show the location of primers. The Hga I site is shown by the broken arrow.
|
|
Subcloning of PCR products.
The PCR fragments were electrophoresed on agarose gel and purified by
using a QIA quick gel extraction kit (Qiagen, Chatsworth, CA), after
which they were introduced into the plasmid vector pCRII by using a TA
cloning kit (Invitrogen, San Diego, CA). Competent cells
(Escherichia coli strain; One Shot competent cell) were transformed with the plasmid, grown in the LB media, and spread on an
agar plate containing kanamycin. The plasmids from single colonies were
prepared separately by the method of Sambrook, et al.19
Sequencing of subcloned DNA.
The DNA sequencing was performed by using a T7 polymerase DNA
sequencing kit (Pharmacia Biotech, Uppsala, Sweden) and universal primers. The reaction mixtures were transferred to an SQ-5500 DNA
Sequencer (Hitachi, Tokyo, Japan).
In vitro transcription/translation analysis.
By using reverse transcriptase (RT)-PCR, we constructed two types of
FXII cDNA (46C-FXII and 46T-FXII) from the liver biopsy sample of a
heterozygote for this polymorphism. The upper primer was designed to be
located in the transcription start site (Fig 1). These PCR products
were introduced into the plasmid vector pCRII mentioned above. By using
nucleotide sequencing, identical sequences in both clones, except in
the position 46, were confirmed. mRNA was created from 1µg of plasmid
of each construct (46C-FXII and 46T-FXII) by using T7 RNA polymerase,
and protein was made by rabbit reticulocyte lysate system and
35S-methionine (Promega, Madison, WI). Synthesized proteins
were applied on 10% SDS-polyacrylamide gel for electrophoresis under reduced conditions. The gel was dried and exposed on an imaging plate
(Fuji Photo Film, Minamiashikaga, Japan) overnight at room temperature
and the amounts of FXII synthesized were quantitated by densitometry.
Statistical analysis.
The data were represented as the means±SD. The differences in
plasma FXII levels between the three groups were determined by
Student's t-test. P values of less than .05 were
considered significant.
| |
RESULTS |
We identified the polymorphism of 46 C/T in exon 1 of the FXII gene as
shown in Fig 2. The substitution of 46 C to
T was located 4 bases upstream from translation initiation codon ATG
(Fig 2). This region corresponded to a Hga I restriction site (GACGC)
that was destroyed by this substitution (46T). Therefore, we
investigated the allele frequency by PCR amplification (primer, U1, and
L1) and Hga I digestion (Fig 3). DNA from
peripheral blood leukocytes was obtained from 76 Orientals and 20 Caucasians. The allele frequency of 46 C/T was 0.27/0.73 in Orientals
(allele number = 152), and conversely, 0.8/0.2 in Caucasians (allele
number = 40).
View larger version (12K):
[in this window]
[in a new window]
| Fig 2.
The nucleotide sequence of 5 end of exon 1 in the
factor XII gene. The polymorphic and Hga I sites are shown by arrows.
Underline indicates the translation initiation codon ATG and 46 C
(polymorphic site). Overline indicates Hga I recognition sequence.
|
|
View larger version (61K):
[in this window]
[in a new window]
| Fig 3.
Hga I restriction analysis of PCR products. (A) 2%
agarose gel electrophoresis of PCR products from genomic DNA in 6 representative samples. Lanes 2 to 5 show heterozygosity for 46C/T.
Lane 6 shows homozygosity for 46C. Lane 7 shows homozygosity for 46T.
Undigested DNA remains as a faint 369 bp in 46C homozygotes even after
a long duration of digestion. A DNA size marker (100bp ladder) was applied in lanes 1 and 8. (B) 5% polyacrylamide gel electrophoresis of
RT-PCR products from liver mRNA in three genetic types for the
polymorphism. Lanes 1 to 3 and 5 show heterozygosity for 46C/T. Lane 6 shows homozygosity for 46T. Lane 7 shows homozygosity for 46C. 53 bp
bands digested by Hga I were barely visible in this study (not shown).
A DNA size marker (100bp ladder) was applied in lane 4.
|
|
It has been reported that plasma FXII levels in Orientals were much
lower than those in Caucasians.15 In addition, because it
was suspected that the nucleotide polymorphism close to the translation
initiation codon ATG may affect the translation efficiency, plasma
levels of FXII activity and antigen were determined in healthy
volunteers with three allele types. There were significant differences
in plasma levels of FXII between these three types: C/C, 170±38%
(178±27%); C/T, 141±29% (123±34%); and T/T, 82±19% (61±11%) [FXII activity in plasma (FXII antigen levels in
plasma)] (Fig 4).
View larger version (18K):
[in this window]
[in a new window]
| Fig 4.
Plasma levels of factor XII activity (A) and antigen (B)
of individuals with 46C/C, 46C/T, or 46T/T. Thirteen Caucasians were included in C/C, 6 in C/T, and 1 in T/T group. The levels of plasma FXII activity and antigen were 150.0±30.3 (n = 20) and 155.4±36.1 (n = 20) in Caucasians, and 125.4±56.3 (n = 31) and 104.7±57.2 (n=20) in Orientals, respectively.
|
|
We studied whether the 46 C/T polymorphism modulates either
transcription or translation. To investigate the transcription effect
of this polymorphism, liver biopsy specimens from seven heterozygotes
for 46 C/T were treated for RNA analysis. Subsequently, the amounts of
RT-PCR products originating from both alleles were assessed by
allele-specific restriction analysis. The 216 and 163 bands were of
identical intensity, suggesting nearly equal transcription from both
alleles (Fig 3B). Therefore, it is not likely that the polymorphism
modulates either transcription in hepatocytes or the stability of mRNA.
In the next experiment, translational efficiency of the polymorphism
was investigated. We constructed two types of FXII cDNA clones
(46C-FXII and 46T-FXII) by using RT-PCR (primer, U2 and L3) from the
liver biopsy sample of a heterozygote for this polymorphism. In vitro
transcription/translation assay showed that the amounts of translated
products from 46C-FXII were three times higher than those from 46T-FXII
for a translation reaction time of 30 minutes, and 1.6 times higher for
the 60-minute reaction (Fig 5). There was
no difference between clones in the amounts of translated products in a
longer reaction (90 minutes). This result indicated that 46 T reduced
the translation efficiency to FXII protein, at least in vitro.
View larger version (57K):
[in this window]
[in a new window]
| Fig 5.
SDS-PAGE analysis of in vitro translated products from
46C- and 46T-FXII cDNA. Incubation times for translation are shown in
the lower portion of the panel. The arrow shows the factor XII
synthesized in vitro. The experiments were repeated with essentially the same results.
|
|
| |
DISCUSSION |
We identified the nucleotide polymorphism (46 C/T) in the FXII gene
that clearly explained the variety of plasma levels of FXII among
individuals. Moreover, 46T was a common polymorphism and was found in
73% of Orientals. Conversely, 80% of Caucasians had the 46C
polymorphism. Therefore, the 46 C/T polymorphism could also explain the
racial differences in plasma FXII levels.
There are some examples of an association between plasma levels of
coagulation factors and polymorphisms in the gene for coagulation factors. There are three polymorphisms in the factor VII gene: decanucleotide insertion in the 5 region of the gene, repeat variation in intron 7, and 353Arg to Gln.20 In
factor V, 1229Hnis to Arg mutation was strongly
related to partial deficiency of factor V.21 Also a
20210G to A transition in the 3-untranslated region
of the prothrombin gene was associated with elevated levels of plasma
prothrombin and an increase in venous thrombosis.22 In
these cases, gene polymorphisms and plasma levels have been discussed
in relation to the development of thromboembolism. However, the
molecular mechanisms of the association of gene polymorphism with
plasma levels were not clearly shown.
As found through the genetic analyses for some human protein
deficiencies, mutant mRNA levels are decreased in some cases by low
transcription efficiency and/or instability of the mutant mRNA.23-25 In our studies, these mechanisms were unlikely
because of the presence of approximately equal amounts of mRNA
transcribed from both alleles in the livers from heterozygotes for the
polymorphism.
The 46T polymorphism creates a codon ATG that is located at 5 bp
upstream from original translation initiation codon ATG. Use of the
putative ATG codon may make a peptide with only two amino acids
(Met-Pro) in a different frame because a TAG stop codon appears 7 bp
downstream from this ATG-initiation codon (Fig 2).
An in vitro transcription/translation study showed that FXII was
produced in lesser amounts from cDNA containing 46T than from that
containing 46C. Even though another ATG codon existed at the
5-site from the original ATG in 46T-FXII, a second (original) ATG initiation codon was also recognized for translation but the amount
of FXII was obviously decreased compared with that obtained with
46C-FXII. Two mechanisms were speculated to explain this phenomenon,
according to the theory of Kozak.26 First, because the
first ATG codon lies in an unfavorable context for initiation, "leaky scanning" enables some ribosomes to reach and initiate at
the second ATG codon. Second, because too little ORF (9bp) is
translated in the frame by using the first ATG codon, 40S ribosomal subunits apparently resume scanning and reinitiate translation further
downstream. Consequently, the two ATG translation initiation codons in
close proximity decreased translation efficiency. Furthermore, 46T
destroys the Kozak's consensus sequence (GCC
AG CCAUGG) for translation initiation
signaling. This may also prevent the proper recognition of the
translation initiation site. In the  -globin gene, it has been
reported that the G to A transition at 26bp 5 to the normal ATG
codon created a cryptic ATG codon that interfered with correct
initiation and caused a -thalassemia intermedia.27
However, to our knowledge, the FXII gene is the first human case in
which a polymorphism in the vicinity of the ATG initiating site reduced
translation efficiency and regulated the plasma concentration of the
translation product.
The prevalence of moderate to severe deficiency of FXII among the
normal Caucasian population is quoted as 1.5% to 3%, which is a
rather high percentage compared with those of other coagulation and
anticoagulation factors.28 We have now proven that the
standard values of the FXII were different between Caucasians and
Orientals owing to this common polymorphism. Therefore, it can be
speculated that the individuals with 46T homozygosity are judged as
FXII deficient under the Caucasian standard. Even in heterozygotes for
46C/T, an additional genetic mutation in 46C allele of FXII gene may
also induce the FXII deficiency state.
Coagulation factor XII is supposed to act in multiple functional
systems involving serine protease activation. In addition, the in vitro
growth and mitotic effects of FXII and FXIIa on Hep G2, a hepatoma cell
line, have been reported as an additional function.29,30
Nevertheless, its physiological roles have remained unknown.
There is controversy over the clinical significance of FXII deficiency
because most of subjects with complete deficiency of FXII have no
clinical manifestations. Some authors31-33 considered FXII
deficiency to be a risk factor for thromboembolism, whereas others34 considered the FXII deficiency to be of minor
importance as a thrombotic risk factor. Hence, further large-scale
study into the association between the development of thromboembolism and this polymorphism may be needed to elucidate the hemostatic function of FXII. In addition, it may be interesting to investigate the
combination effect of such common genetic polymorphisms, including Factor V Leiden and 20210 G to A in prothrombin gene, on the thrombotic predisposition.
| |
FOOTNOTES |
Submitted July 17, 1997;
accepted August 27, 1997.
Address correspondence to Takashi Okamura, MD, First Department of
Internal Medicine,Faculty of Medicine, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-82, Japan.
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.
| |
REFERENCES |
1.
Kluft C,
Dooijewaard G,
Emeis JJ:
Role of the contact system fibrinolysis.
Semin Thromb Hemost
13:50,
1987[Medline]
[Order article via Infotrieve]
2. Magnusson S, Sottruo-Jensen L, Petersen TE, Dudeke-Wojciechowska
G, Claeys H: Homologous "kringle" structures common to
plasminogen and prothrombin. Substrate specificity of enzymes activating prothrombin and plasminogen, in Ribbons DW, Brew K (eds):
Proteolysis and Physiological Regulation, vol 11. New York, NY,
Academic, 1976, p 203
3.
Ratnoff OD,
Colopy JE:
A familial hemorrhagic trait associated with a deficiency of a clot-promoting fraction of plasma.
J Clin Invest
34:602,
1955
4.
Saito H:
Contact factors in health and disease.
Semin Thromb Hemost
13:36,
1987[Medline]
[Order article via Infotrieve]
5.
Ratnoff OD,
Busse RJ,
Sheron R:
The demise of John Hageman.
N Engl J Med
279:420,
1963
6.
Goodnough LT,
Saito H,
Ratnoff OD:
Thrombosis or myocardial infarction in congenital clotting factors abnormalities and chronic thrombocytopenias: A report of 21 patients and a review of 50 previously reported cases.
Medicine
62:248,
1983[Medline]
[Order article via Infotrieve]
7.
Cool DE,
Edgell CJS,
Louie GV,
Zoller MJ,
Brayer GD,
MacGillivray RTA:
Characterization of human blood coagulation factor XII cDNA. Prediction of the primary structure of factor XII and the tertiary structure of -factor XIIa.
J Biol Chem
260:13666,
1985[Abstract/Free Full Text]
8.
Que BG,
Davie EW:
Characterization of a cDNA coding for human factor XII (Hageman factor).
Biochemistry
25:1525,
1986[Medline]
[Order article via Infotrieve]
9.
Tripodi M,
Citarella F,
Guida S,
Galeffi P,
Fantoni A,
Cortese R:
cDNA sequence coding for human coagulation factor XII (Hageman).
Nucleic Acids Res
14:3146,
1986[Free Full Text]
10.
Clark BJ,
Cote H,
Cool DE,
Clark-Lewis I,
Saito H,
Pixley RA,
Colman RW,
MacGillivray RTA:
Mapping of a putative surface-binding site of human coagulation factor XII.
J Biol Chem
264:11497,
1989[Abstract/Free Full Text]
11.
Cool DE,
MacGillivray RTA:
Characterization of the human blood coagulation factor XII gene.
J Biol Chem
262:13662,
1987[Abstract/Free Full Text]
12.
Royle NJ,
Nigli M,
Cool D,
MacGillivray RTA,
Hamerton JL:
Structural gene encoding human factor XII is located at 5q33-qter.
Somat Cell Mol Genet
14:217,
1988[Medline]
[Order article via Infotrieve]
13.
Revak SD,
Cochrane CG,
Griffin JH:
Structural changes accompanying enzymatic activation of human Hageman factor.
J Clin Invest
54:619,
1974
14.
Saito H,
Ratnoff OD,
Pensky J:
Radioimmunoassay of human Hageman factor (factor XII).
J Lab Clin Med
88:506,
1976[Medline]
[Order article via Infotrieve]
15.
Gordon EM,
Donaldson VH,
Saito H,
Su E,
Ratnoff OD:
Reduced titers of Hageman factor (Factor XII) in Orientals.
Ann Intern Med
95:697,
1981
16. (abstr)
Kanaji T,
Okamura T,
Niho Y,
Sugiyama M:
Molecular analysis of a family with factor XII deficiency. Identification of 126 Arg to Pro substitution.
Blood
86:876a,
1995
17.
Dati F,
Barthels M,
Conard J,
Flückiger J,
Girolami A,
Hänseler E,
Huber J,
Keller F,
Kolde H-J,
Muller-Berghaus G,
Samama M,
Thiel W:
Multicenter evaluation of a chromogenic substrate method for photometric determination of prothrombin time.
Thromb Haemost
58:856,
1987[Medline]
[Order article via Infotrieve]
18.
Laurell,
CB:
Quantitative estimation of proteins by electrophoresis in agarose gel containing antibodies.
Anal Biochem
15:45,
1966[Medline]
[Order article via Infotrieve]
19. Sambrook J, Fritsch EF, Maniatis T: Molecular Cloning. A
Laboratory Manual, 2nd Ed. New York, Cold Spring Harbor Laboratory
Press, 1989
20.
Bernardi F,
Marchetti G,
Pinotti M,
Arcieri P,
Barnocini C,
Papacchini M,
Zepponi E,
Urscino N,
Chiarotti F,
Mariani G:
Factor VII gene polymorphisms contribute about one third of the factor VII level variation in plasma.
Arterioscler Thromb Vasc Biol
16:72,
1996
21.
Lunghi B,
Iacoviello L,
Gemmati D,
Dilasio MG,
Castoldi E,
Pinotti M,
Castaman G,
Redaelli R,
Mariani G,
Marchetti G,
Bernardi F:
Detection of new polymorphic markers in the factor V gene: Association with factor V levels in plasma.
Thromb Haemost
75:45,
1996[Medline]
[Order article via Infotrieve]
22.
Poort SR,
Rosendaal FR,
Reitsma PH,
Bertina RM:
A common genetic variation in the 3-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and increase in venous thrombosis.
Blood
88:3698,
1996[Abstract/Free Full Text]
23.
Cooper DN:
Human gene mutations affecting RNA processing and translation.
Ann Med
25:11,
1993[Medline]
[Order article via Infotrieve]
24.
Eikenboom JCJ,
Ploos van Amstel HK,
Reitsma PH,
Briet E:
Mutations in severe type II von Willebrand's disease in the Dutch population: Candidate missense and nonsense mutations associated with reduced levels of von Willebrand factor messenger RNA.
Thromb Haemost
68:448,
1992[Medline]
[Order article via Infotrieve]
25.
Yamazaki T,
Hamaguchi M,
Katsumi A,
Kagami K,
Kojima T,
Takamatsu J,
Saito H:
A Quantitative protein S deficiency associated with a novel nonsense mutation and markedly reduced levels of mutated mRNA.
Thromb Haemost
74:590,
1995[Medline]
[Order article via Infotrieve]
26.
Kozak M:
The scanning model for translation: An update.
J Cell Biol
108:229,
1989[Abstract/Free Full Text]
27.
Cai S-P,
Eng B,
Francombe WH,
Olivieri NF,
Kendall AG,
Waye JS,
Chui DHK:
Two novel -thalassemia mutations in the 5 and 3 noncoding regions of the -globin gene.
Blood
79:1342,
1992[Abstract/Free Full Text]
28.
Halbmayer W-M,
Haushofer A,
Schön R,
Mannhalter C,
Strohmer E,
Baumgarten K,
Fischer M:
The prevalence of moderate and severe FXII (Hageman factor) deficiency among the normal population: Evaluation of the incidence of FXII deficiency among 300 healthy blood donors.
Thromb Haemost
71:68,
1994[Medline]
[Order article via Infotrieve]
29.
Schmeidler-Sapiro KT,
Ratnoff OD,
Gordon EM:
Mitogenic effects of coagulation factor XII and factor XIIa on HepG2 cells.
Proc Natl Acad Sci USA
88:4382,
1991[Abstract/Free Full Text]
30.
Gordon EM,
Venkatesan N,
Salazar R,
Tang H,
Schmeidler-Sapiro K,
Buckley S,
Warburton D,
Hall FL:
Factor XII-induced mitogenesis is mediated via a distinct signal transduction pathway that activates a mitogen-activated protein kinase.
Proc Natl Acad Sci USA
93:2174,
1996[Abstract/Free Full Text]
31.
Lämmle B,
Wuillemin WA,
Huber I,
Krauskopf M,
Zürcher C,
Pflugshaupt R,
Furlan M:
Thromboembolism and bleeding tendency in congenital factor XII deficiency-A study on 74 subjects from 14 Swiss families.
Thromb Haemost
65:117,
1991[Medline]
[Order article via Infotrieve]
32.
Halbmayer W-M,
Mannhalter C,
Feichtinger C,
Rubi K,
Fischer M:
The prevalence of factor XII deficiency in 103 orally anticoagulated outpatients suffering from recurrent venous and/or arterial thromboembolism.
Thromb Haemost
68:285,
1992[Medline]
[Order article via Infotrieve]
33.
Winter M,
Gallimore M,
Jones DW:
Should factor XII assays be included in thrombophilia screening?
Lancet
346:52,
1995[Medline]
[Order article via Infotrieve]
34.
Koster T,
Rosendaal FR,
Briet E,
Vandenbroucke JP:
John Hageman's factor and deep-vein thrombosis: Leiden Thrombophilia study.
Br J Haematol
87:422,
1994[Medline]
[Order article via Infotrieve]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
F. Calafell, L. Almasy, M. Sabater-Lleal, A. Buil, C. Mordillo, A. Ramirez-Soriano, M. Sikora, J. C. Souto, J. Blangero, J. Fontcuberta, et al.
Sequence variation and genetic evolution at the human F12 locus: mapping quantitative trait nucleotides that influence FXII plasma levels
Hum. Mol. Genet.,
December 2, 2009;
(2009)
ddp517v2.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. E. Calvo, D. J. Pagliarini, and V. K. Mootha
Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans
PNAS,
May 5, 2009;
106(18):
7507 - 7512.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. H. Reuner, E. Jenetzky, A. Aleu, F. Litfin, P. Mellado, M. Kloss, E. Juttler, A. J. Grau, H. Rickmann, H. Patscheke, et al.
Factor XII C46T gene polymorphism and the risk of cerebral venous thrombosis
Neurology,
January 8, 2008;
70(2):
129 - 132.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Park, H. S. Chang, C.-S. Park, A.-S. Jang, B. L. Park, T. Y. Rhim, S.-T. Uh, Y. H. Kim, I. Y. Chung, and H. D. Shin
Association Analysis of CD40 Polymorphisms with Asthma and the Level of Serum Total IgE
Am. J. Respir. Crit. Care Med.,
April 15, 2007;
175(8):
775 - 782.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Kimura, S. Honda, T. Kawasaki, H. Tsuji, S. Madoiwa, Y. Sakata, T. Kojima, M. Murata, K. Nishigami, M. Chiku, et al.
Protein S-K196E mutation as a genetic risk factor for deep vein thrombosis in Japanese patients
Blood,
February 15, 2006;
107(4):
1737 - 1738.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Jacobson, E. Concepcion, T. Oashi, and Y. Tomer
A Graves' Disease-Associated Kozak Sequence Single-Nucleotide Polymorphism Enhances the Efficiency of CD40 Gene Translation: A Case for Translational Pathophysiology
Endocrinology,
June 1, 2005;
146(6):
2684 - 2691.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Girolami, M. Morello, B. Girolami, A. M. Lombardi, and C. Bertolo
Myocardial Infarction and Arterial Thrombosis in Severe (Homozygous) FXII Deficiency: No Apparent Causative Relation
Clinical and Applied Thrombosis/Hemostasis,
January 1, 2005;
11(1):
49 - 53.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A. Santamaria, J. Mateo, I. Tirado, A. Oliver, R. Belvis, J. Marti-Fabregas, R. Felices, J. M. Soria, J. C. Souto, and J. Fontcuberta
Homozygosity of the T Allele of the 46 C->T Polymorphism in the F12 Gene Is a Risk Factor for Ischemic Stroke in the Spanish Population
Stroke,
August 1, 2004;
35(8):
1795 - 1799.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Fujihara, M. Tozuka, K. Yamauchi, I. Ueno, N. Urasawa, S. Ishikawa, M. Hirota-Kawadobora, N. Okumura, H. Hidaka, and T. Katsuyama
Characterization of Factor XII Tenri, a Rare CRM-Negative Factor XII Deficiency
Ann. Clin. Lab. Sci.,
April 1, 2004;
34(2):
218 - 225.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Y. Park, S. H. Park, J. E. Choi, S. Y. Lee, H.-S. Jeon, S. I. Cha, C. H. Kim, J.-H. Park, S. Kam, R. W. Park, et al.
Polymorphisms of the DNA Repair Gene Xeroderma Pigmentosum Group A and Risk of Primary Lung Cancer
Cancer Epidemiol. Biomarkers Prev.,
October 1, 2002;
11(10):
993 - 997.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Gonzalez-Conejero, J. Corral, V. Roldan, C. Martinez, F. Marin, J. Rivera, J. A. Iniesta, M. L. Lozano, P. Marco, and V. Vicente
A common polymorphism in the annexin V Kozak sequence (-1C>T) increases translation efficiency and plasma levels of annexin V, and decreases the risk of myocardial infarction in young patients
Blood,
August 28, 2002;
100(6):
2081 - 2086.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Orth, S. Westphal, J. Dierkes, C. Luley, and K. Schlatterer
Rapid Factor XII (46C{->}T) Genotyping by Fluorescence Resonance Energy Transfer in Patients with Coronary Artery Disease or Thrombophilia
Clin. Chem.,
June 1, 2001;
47(6):
1117 - 1119.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. Williams and P. F. Bray
Genetics of Arterial Prothrombotic Risk States
Experimental Biology and Medicine,
May 1, 2001;
226(5):
409 - 419.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
V. Afshar-Kharghan, C. Q. Li, M. Khoshnevis-Asl, and J. A. Lopez
Kozak Sequence Polymorphism of the Glycoprotein (GP) Ibalpha Gene Is a Major Determinant of the Plasma Membrane Levels of the Platelet GP Ib-IX-V Complex
Blood,
July 1, 1999;
94(1):
186 - 191.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kondo, F. Tokunaga, S. Kawano, Y. Oono, S. Kumagai, and T. Koide
Factor XII Tenri, a Novel Cross-Reacting Material Negative Factor XII Deficiency, Occurs Through a Proteasome-Mediated Degradation
Blood,
June 15, 1999;
93(12):
4300 - 4308.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract