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Toru Nakabayashi, Kazuhiro Mizukami, Sumiyoshi Naitoh, Mika Takeda, Yasuo Shikamoto, Takafumi Nakagawa, Hiroki Kaneko, Takashi Tarumi, Itaru Mizoguchi, Hiroshi Mizuno, Masahiro Ieko, Takao Koike
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
Interaction of the -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 to A 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 25Lys/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 25Lys mutation induces type IIb protein C deficiency in individuals.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 94, 11/2005
Pages: 942 - 950