A Novel Polymorphism in Exon 10 of the Factor V Gene Inducing an Amino Acid Replacement of Arginine to Lysine at Codon 485

Introduction: Acute pulmonary thromboembolism (PTE) presents with wide spectrum and has variable prognosis. Factor V Leiden (FVL) is the most common inherited thrombophilia, with a prevalence of 3%-7% in the general US population, approximately 5% in Whites, 2.2% in Hispanics and 1.2% in Blacks. PTE most commonly originates from venous thrombosis. The occurrence of venous thromboembolism is a culmination of environmental and genetic risk factors. The current study was sought to identify the mutations in exon-10 of FV gene in patients with PTE.<br /> Methods: Sixty cases diagnosed with PTE and 50 healthy controls were enrolled in the present study. Mutation studies in exon-10 of Factor V gene included PCR-DNA sequencing method.<br /> Results: Of 60 patients, we found two novel transition type point mutations: c.1538 G>A and c.1601 G>A in exon-10 of Factor V which is responsible for the cleavage site for aPC. These point mutations resulted in single amino acid change in protein sequence at p.Arg513Lys and p.Arg534Gln respectively. These mutations prevent efficient inactivation of Factor V and Factor V remains active which facilitates over production of thrombin leading to generation of excess fibrin and excess coagulation which results in deep vein thrombosis and PTE.<br /> Conclusion: We report two novel point mutations (c.1538 G>A and c.1601 G>A) in exon-10 of Factor V gene in Indian patients with PTE.

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Elevated Levels of Prothrombin Activation Fragment 1+2 in Plasma from Patients with Heterozygous Arg506 to Gin Mutation in the Factor V Gene (APC-Resistance) and/or Inherited Protein S Deficiency

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650259 ◽

1996 ◽

Vol 75 (02) ◽

pp. 270-274 ◽

Cited By ~ 57

Author(s):

Benget Zöller ◽

Johan Holm ◽

Peter Svensson ◽

Björn Dahlbäck

Keyword(s):

Plasma Concentration ◽

Protein C ◽

Protein S ◽

Factor V ◽

Protein S Deficiency ◽

Apc Resistance ◽

S Deficiency ◽

Increased Risk ◽

Factor V Gene ◽

V Gene

SummaryInherited resistance to activated protein C (APC-resistance), caused by a point mutation in the factor V gene leading to replacement of Arg(R)506 with a Gin (Q), and inherited protein S deficiency are associated with functional impairment of the protein C anticoagulant system, yielding lifelong hypercoagulability and increased risk of thrombosis. APC-resistance is often an additional genetic risk factor in thrombosis-prone protein S deficient families. The plasma concentration of prothrombin fragment 1+2 (F1+2), which is a marker of hyper-coagulable states, was measured in 205 members of 34 thrombosis-prone families harbouring the Arg506 to Gin mutation (APC-resistance) and/or inherited protein S deficiency. The plasma concentration of F1+2 was significantly higher both in 38 individuals carrying the FV:Q506 mutation in heterozygous state (1.7 ± 0.7 nM; mean ± SD) and in 48 protein S deficient cases (1.9 ± 0.9 nM), than in 100 unaffected relatives (1.3 ±0.5 nM). Warfarin therapy decreased the F1+2 levels, even in those four patients who had combined defects (0.5 ± 0.3 nM). Our results agree with the hypothesis that individuals with APC-resistance or protein S deficiency have an imbalance between pro- and anti-coagulant forces leading to increased thrombin generation and a hypercoagulable state.

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Factor V Kuwait: A Novel Mutation in the Coagulation Factor V Gene Discovered in Kuwait

Medical Principles and Practice ◽

10.1159/000090912 ◽

2006 ◽

Vol 15 (2) ◽

pp. 102-105

Author(s):

Mehrez M. Jadaon ◽

Ali A. Dashti ◽

Hend L. Lewis

Keyword(s):

Novel Mutation ◽

Coagulation Factor ◽

Factor V ◽

Coagulation Factor V ◽

Factor V Gene ◽

V Gene

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A Factor V Genetic Component Differing From Factor V R506Q Contributes to the Activated Protein C Resistance Phenotype

Blood ◽

10.1182/blood.v90.4.1552 ◽

1997 ◽

Vol 90 (4) ◽

pp. 1552-1557 ◽

Cited By ~ 127

Author(s):

F. Bernardi ◽

E.M. Faioni ◽

E. Castoldi ◽

B. Lunghi ◽

G. Castaman ◽

...

Keyword(s):

Venous Thromboembolism ◽

Protein C ◽

Activated Protein C ◽

Functional Assay ◽

Factor V ◽

Resistance Phenotype ◽

Apc Resistance ◽

Genetic Components ◽

Factor V Gene ◽

V Gene

AbstractFactor V gene polymorphisms were investigated to detect components that may contribute to the activated protein C (APC) resistance phenotype in patients with venous thromboembolism. A specific factor V gene haplotype (HR2) was defined by six polymorphisms and its frequency was found to be similar in normal subjects coming from Italy (0.08), India (0.1), and Somalia (0.08), indicating that it was originated by ancestral mutational events. The relationship between the distribution of normalized APC ratios obtained with the functional assay and haplotype frequency was analyzed in patients heterozygous for factor V R506Q (factor V Leiden). The HR2 haplotype was significantly more frequent in patients with ratios below the 15th percentile than in those with higher ratios or in normal controls. Moreover, the study of 10 patients with APC resistance in the absence of the factor V R506Q mutation showed a 50-fold higher frequency of HR2 homozygotes. The HR2 haplotype was associated with significantly lower APC ratios both in patients with venous thromboembolism and in age- and sex-matched controls. However, the two groups showed similar HR2 haplotype frequencies. Plasma mixing experiments showed that an artificially created double heterozygote for the factor V R506Q mutation and the HR2 haplotype had an APC ratio lower than that expected for a simple R506Q heterozygote. Time-course experiments evaluating the decay of factor V in plasma showed the normal stability of the molecule encoded by the factor V gene marked by the HR2 haplotype, which ruled out the presence of a pseudo-homozygous APC resistance mechanism. Our results provide new insights into the presence of factor V genetic components other than the factor V R506Q that are able to contribute to the APC resistance phenotype in patients with venous thromboembolism.

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Lack of Activated Protein C Resistance in Healthy Hong Kong Chinese Blood Donors - Correlation with Absence of Arg506-Gln Mutation of Factor V Gene

Thrombosis and Haemostasis ◽

10.1055/s-0038-1665404 ◽

1996 ◽

Vol 75 (03) ◽

pp. 522-523 ◽

Cited By ~ 26

Author(s):

L C Chan ◽

C Bourke ◽

C K Lam ◽

H W Liu ◽

S Brookes ◽

...

Keyword(s):

Hong Kong ◽

Protein C ◽

Blood Donors ◽

Activated Protein C ◽

Hong Kong Chinese ◽

Factor V ◽

Activated Protein C Resistance ◽

Factor V Gene ◽

V Gene

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A Novel Mutation of Arg306 of Factor V Gene in Hong Kong Chinese

Blood ◽

10.1182/blood.v91.4.1135 ◽

1998 ◽

Vol 91 (4) ◽

pp. 1135-1139 ◽

Cited By ~ 137

Author(s):

W.P. Chan ◽

C.K. Lee ◽

Y.L. Kwong ◽

C.K. Lam ◽

Raymond Liang

Keyword(s):

Hong Kong ◽

Dna Sequence ◽

Denaturing Gradient Gel Electrophoresis ◽

Novel Mutation ◽

Clinical Importance ◽

Hong Kong Chinese ◽

Factor V ◽

Mutation Site ◽

Factor V Gene ◽

V Gene

AbstractWe 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 G1691→A (Arg 506→Gln) mutation in exon 10 was not detectable in any of the 83 subjects. However, a high allelic frequency for the G1628→A (Arg 485→Lys) substitution was detectable in the same exon. We have also identified a novel DNA sequence mutation (A1090→G) in exon 7 that resulted in Arg 306→Gly 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 506→Gln mutation was rarely found in the Hong Kong Chinese population, a different mutation site such as A 1090→G in exon 7 of the factor V gene (Arg 306) may be of clinical importance.

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