Prevalence of genetic mutations in protein S, protein C and antithrombin genes in Japanese patients with deep vein thrombosis

Toshiyuki Miyata, Yukiko Sato, Junko Ishikawa, Hiromi Okada, Satoshi Takeshita, Toshiyuki Sakata, Koichi Kokame, Rina Kimura, Shigenori Honda, Tomio Kawasaki, Etsuji Suehisa, Hajime Tsuji, Seiji Madoiwa, Yoichi Sakata, Tetsuhito Kojima, Mitsuru Murata, Yasuo Ikeda

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Introduction: Genetic deficiencies of PROS1, PROC, and SERPINC1 (antithrombin) are risk factors for deep vein thrombosis (DVT). Diagnosis of the inherited deficiencies of these three genes is sometimes difficult because of the phenotypic variability. This study was undertaken to reveal the frequency of nonsynonymous mutations of these three genes in Japanese DVT patients. Patients/Methods: One hundred seventy-three DVT patients were registered by the Sub-group of Blood Coagulation Abnormality, from the Study Group of Research on Measures for Intractable Diseases. We sequenced the entire coding regions of the three genes in all DNA samples and identified the nonsynonymous mutations. Results and Conclusions: For PROS1 we identified 15 nonsynonymous mutations in 28 DVT patients; for PROC, 10 nonsynonymous mutations in 17 patients; and for SERPINC1, 13 nonsynonymous mutations in 14 patients. Five patients had two mutations in PROS1 and PROC, and all of them had PROS1 K196E mutation. We previously identified one patient with a large PROS1 gene deletion. Thus, 55 out of 173 patients (32%) carried at least one genetic defect in the three genes. The PROS1 K196E mutation found in 15 Japanese DVT patients was the most prevalent. Mutations of PROC K193del and V339M were the second, each found in four patients. Our data suggested that the PROC K193del mutation caused the loss of the anticoagulant activity but not the amidolytic activity. Our effort is the first DNA resequencing study to identify the genetic variations in DVT patients without any consideration of their plasma activities and antigens. To minimize selection bias in a future evaluation of the contribution of genetic deficiency to DVT, we must recruit patients consecutively.

Original languageEnglish
Pages (from-to)14-18
Number of pages5
JournalThrombosis Research
Volume124
Issue number1
DOIs
Publication statusPublished - 2009 May

Fingerprint

Antithrombins
Protein S
Protein C
Venous Thrombosis
Mutation
Genes
Selection Bias
DNA
Gene Deletion
Blood Coagulation
Mutation Rate
Anticoagulants

Keywords

  • Antithrombin
  • Deep vein thrombosis
  • Nonsynonymous mutation
  • Protein C
  • Protein S
  • Resequencing

ASJC Scopus subject areas

  • Hematology

Cite this

Prevalence of genetic mutations in protein S, protein C and antithrombin genes in Japanese patients with deep vein thrombosis. / Miyata, Toshiyuki; Sato, Yukiko; Ishikawa, Junko; Okada, Hiromi; Takeshita, Satoshi; Sakata, Toshiyuki; Kokame, Koichi; Kimura, Rina; Honda, Shigenori; Kawasaki, Tomio; Suehisa, Etsuji; Tsuji, Hajime; Madoiwa, Seiji; Sakata, Yoichi; Kojima, Tetsuhito; Murata, Mitsuru; Ikeda, Yasuo.

In: Thrombosis Research, Vol. 124, No. 1, 05.2009, p. 14-18.

Research output: Contribution to journalArticle

Miyata, T, Sato, Y, Ishikawa, J, Okada, H, Takeshita, S, Sakata, T, Kokame, K, Kimura, R, Honda, S, Kawasaki, T, Suehisa, E, Tsuji, H, Madoiwa, S, Sakata, Y, Kojima, T, Murata, M & Ikeda, Y 2009, 'Prevalence of genetic mutations in protein S, protein C and antithrombin genes in Japanese patients with deep vein thrombosis', Thrombosis Research, vol. 124, no. 1, pp. 14-18. https://doi.org/10.1016/j.thromres.2008.08.020
Miyata, Toshiyuki ; Sato, Yukiko ; Ishikawa, Junko ; Okada, Hiromi ; Takeshita, Satoshi ; Sakata, Toshiyuki ; Kokame, Koichi ; Kimura, Rina ; Honda, Shigenori ; Kawasaki, Tomio ; Suehisa, Etsuji ; Tsuji, Hajime ; Madoiwa, Seiji ; Sakata, Yoichi ; Kojima, Tetsuhito ; Murata, Mitsuru ; Ikeda, Yasuo. / Prevalence of genetic mutations in protein S, protein C and antithrombin genes in Japanese patients with deep vein thrombosis. In: Thrombosis Research. 2009 ; Vol. 124, No. 1. pp. 14-18.
@article{f6e29cddd12e4929a3e22a9271e75fa7,
title = "Prevalence of genetic mutations in protein S, protein C and antithrombin genes in Japanese patients with deep vein thrombosis",
abstract = "Introduction: Genetic deficiencies of PROS1, PROC, and SERPINC1 (antithrombin) are risk factors for deep vein thrombosis (DVT). Diagnosis of the inherited deficiencies of these three genes is sometimes difficult because of the phenotypic variability. This study was undertaken to reveal the frequency of nonsynonymous mutations of these three genes in Japanese DVT patients. Patients/Methods: One hundred seventy-three DVT patients were registered by the Sub-group of Blood Coagulation Abnormality, from the Study Group of Research on Measures for Intractable Diseases. We sequenced the entire coding regions of the three genes in all DNA samples and identified the nonsynonymous mutations. Results and Conclusions: For PROS1 we identified 15 nonsynonymous mutations in 28 DVT patients; for PROC, 10 nonsynonymous mutations in 17 patients; and for SERPINC1, 13 nonsynonymous mutations in 14 patients. Five patients had two mutations in PROS1 and PROC, and all of them had PROS1 K196E mutation. We previously identified one patient with a large PROS1 gene deletion. Thus, 55 out of 173 patients (32{\%}) carried at least one genetic defect in the three genes. The PROS1 K196E mutation found in 15 Japanese DVT patients was the most prevalent. Mutations of PROC K193del and V339M were the second, each found in four patients. Our data suggested that the PROC K193del mutation caused the loss of the anticoagulant activity but not the amidolytic activity. Our effort is the first DNA resequencing study to identify the genetic variations in DVT patients without any consideration of their plasma activities and antigens. To minimize selection bias in a future evaluation of the contribution of genetic deficiency to DVT, we must recruit patients consecutively.",
keywords = "Antithrombin, Deep vein thrombosis, Nonsynonymous mutation, Protein C, Protein S, Resequencing",
author = "Toshiyuki Miyata and Yukiko Sato and Junko Ishikawa and Hiromi Okada and Satoshi Takeshita and Toshiyuki Sakata and Koichi Kokame and Rina Kimura and Shigenori Honda and Tomio Kawasaki and Etsuji Suehisa and Hajime Tsuji and Seiji Madoiwa and Yoichi Sakata and Tetsuhito Kojima and Mitsuru Murata and Yasuo Ikeda",
year = "2009",
month = "5",
doi = "10.1016/j.thromres.2008.08.020",
language = "English",
volume = "124",
pages = "14--18",
journal = "Thrombosis Research",
issn = "0049-3848",
publisher = "Elsevier Limited",
number = "1",

}

TY - JOUR

T1 - Prevalence of genetic mutations in protein S, protein C and antithrombin genes in Japanese patients with deep vein thrombosis

AU - Miyata, Toshiyuki

AU - Sato, Yukiko

AU - Ishikawa, Junko

AU - Okada, Hiromi

AU - Takeshita, Satoshi

AU - Sakata, Toshiyuki

AU - Kokame, Koichi

AU - Kimura, Rina

AU - Honda, Shigenori

AU - Kawasaki, Tomio

AU - Suehisa, Etsuji

AU - Tsuji, Hajime

AU - Madoiwa, Seiji

AU - Sakata, Yoichi

AU - Kojima, Tetsuhito

AU - Murata, Mitsuru

AU - Ikeda, Yasuo

PY - 2009/5

Y1 - 2009/5

N2 - Introduction: Genetic deficiencies of PROS1, PROC, and SERPINC1 (antithrombin) are risk factors for deep vein thrombosis (DVT). Diagnosis of the inherited deficiencies of these three genes is sometimes difficult because of the phenotypic variability. This study was undertaken to reveal the frequency of nonsynonymous mutations of these three genes in Japanese DVT patients. Patients/Methods: One hundred seventy-three DVT patients were registered by the Sub-group of Blood Coagulation Abnormality, from the Study Group of Research on Measures for Intractable Diseases. We sequenced the entire coding regions of the three genes in all DNA samples and identified the nonsynonymous mutations. Results and Conclusions: For PROS1 we identified 15 nonsynonymous mutations in 28 DVT patients; for PROC, 10 nonsynonymous mutations in 17 patients; and for SERPINC1, 13 nonsynonymous mutations in 14 patients. Five patients had two mutations in PROS1 and PROC, and all of them had PROS1 K196E mutation. We previously identified one patient with a large PROS1 gene deletion. Thus, 55 out of 173 patients (32%) carried at least one genetic defect in the three genes. The PROS1 K196E mutation found in 15 Japanese DVT patients was the most prevalent. Mutations of PROC K193del and V339M were the second, each found in four patients. Our data suggested that the PROC K193del mutation caused the loss of the anticoagulant activity but not the amidolytic activity. Our effort is the first DNA resequencing study to identify the genetic variations in DVT patients without any consideration of their plasma activities and antigens. To minimize selection bias in a future evaluation of the contribution of genetic deficiency to DVT, we must recruit patients consecutively.

AB - Introduction: Genetic deficiencies of PROS1, PROC, and SERPINC1 (antithrombin) are risk factors for deep vein thrombosis (DVT). Diagnosis of the inherited deficiencies of these three genes is sometimes difficult because of the phenotypic variability. This study was undertaken to reveal the frequency of nonsynonymous mutations of these three genes in Japanese DVT patients. Patients/Methods: One hundred seventy-three DVT patients were registered by the Sub-group of Blood Coagulation Abnormality, from the Study Group of Research on Measures for Intractable Diseases. We sequenced the entire coding regions of the three genes in all DNA samples and identified the nonsynonymous mutations. Results and Conclusions: For PROS1 we identified 15 nonsynonymous mutations in 28 DVT patients; for PROC, 10 nonsynonymous mutations in 17 patients; and for SERPINC1, 13 nonsynonymous mutations in 14 patients. Five patients had two mutations in PROS1 and PROC, and all of them had PROS1 K196E mutation. We previously identified one patient with a large PROS1 gene deletion. Thus, 55 out of 173 patients (32%) carried at least one genetic defect in the three genes. The PROS1 K196E mutation found in 15 Japanese DVT patients was the most prevalent. Mutations of PROC K193del and V339M were the second, each found in four patients. Our data suggested that the PROC K193del mutation caused the loss of the anticoagulant activity but not the amidolytic activity. Our effort is the first DNA resequencing study to identify the genetic variations in DVT patients without any consideration of their plasma activities and antigens. To minimize selection bias in a future evaluation of the contribution of genetic deficiency to DVT, we must recruit patients consecutively.

KW - Antithrombin

KW - Deep vein thrombosis

KW - Nonsynonymous mutation

KW - Protein C

KW - Protein S

KW - Resequencing

UR - http://www.scopus.com/inward/record.url?scp=64649084828&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=64649084828&partnerID=8YFLogxK

U2 - 10.1016/j.thromres.2008.08.020

DO - 10.1016/j.thromres.2008.08.020

M3 - Article

C2 - 18954896

AN - SCOPUS:64649084828

VL - 124

SP - 14

EP - 18

JO - Thrombosis Research

JF - Thrombosis Research

SN - 0049-3848

IS - 1

ER -