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Thromb Haemost 2005; 94(05): 942-950
DOI: 10.1160/TH05-05-0326
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Protein C Sapporo (protein C Glu 25 → Lys): A heterozygous missense mutation in the Gla domain provides new insight into the interaction between protein C and endothelial protein C receptor

Toru Nakabayashi
1   Department of Internal Medicine, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan
,
Kazuhiro Mizukami
2   Department of Orthodontics, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan
,
Sumiyoshi Naitoh
3   Department of Clinical Laboratory, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan
,
Mika Takeda
3   Department of Clinical Laboratory, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan
,
Yasuo Shikamoto
4   Valway Technology Center, NEC Soft, Ltd., Tsukuba, Ibaraki, Japan
,
Takafumi Nakagawa
4   Valway Technology Center, NEC Soft, Ltd., Tsukuba, Ibaraki, Japan
,
Hiroki Kaneko
5   Department of Applied Physics, College of Humanities and Sciences, Nihon University, Tokyo, Japan
,
Takashi Tarumi
1   Department of Internal Medicine, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan
,
Itaru Mizoguchi
2   Department of Orthodontics, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan
,
Hiroshi Mizuno
4   Valway Technology Center, NEC Soft, Ltd., Tsukuba, Ibaraki, Japan
,
Masahiro Ieko
1   Department of Internal Medicine, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan
3   Department of Clinical Laboratory, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan
,
Takao Koike
6   Department of Medicine II, Hokkaido University School of Medicine, Sapporo, Japan
› Author Affiliations Financial support: This work was supported in part by the “Academic Frontier” Project for Private Universities: matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science and Technology), 2002–2006.
Further Information

Publication History

Received: 12 May 2005

Accepted after revision: 31 August 2005

Publication Date:
14 December 2017 (online)

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Summary

Interaction of the γ-carboxyglutamic acid (Gla) domain of protein C with endothelial protein C receptor (EPCR) is a critical step for efficient activation of protein C, though interactions by mutants in the Gla domain of protein C with EPCR have been rarely evaluated. We identified a 44-year-old Japanese woman with a history of recurrent thromboembolism as an inherited missense mutation, the first such case reported in Japan, which involved a protein C Gla 25 mutation. Total protein C antigen and Gla protein C antigen levels in the proband were normal. Protein C activity measured with an anticoagulant assay was reduced, whereas that measured with an amidolytic assay was normal. She was therefore phenotypically diagnosed as type IIb protein C deficiency. Direct sequencing of the PCR fragments revealed a heterozygous G toA transition at nucleotide position 1462 in exon 3, which predicted an amino acid substitution of Glu 25 by Lys. Her mother and one son were also heterozygous for this mutation. A molecular dynamics simulation of Gla 25→Lys/EPCR complex in water suggested that the affinity between the molecules was decreased compared to the wild type Gla domain/EPCR complex. Since Gla 25 has been shown to play an important role in protein C function, not only in membrane phospholipid binding but also in binding to EPCR, our findings provide new insight into the mechanism by which the Glu 25→Lys mutation induces type IIb protein C deficiency in individuals.

Keywords

Protein C deficiency - type IIb deficiency - protein C Sapporo - Gla domain (γ-carboxyglutamic acid domain) - EPCR (endothelial protein C receptor)
 

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