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Thromb Haemost 2002; 88(04): 632-638
DOI: 10.1055/s-0037-1613267
Review Article
Schattauer GmbH

Protein C Deficiency caused by Homozygosity for a Novel PROC D180G Mutation – in vitro Expression and Structural Analysis of the Mutation

Bent Lind
1   Department of Clinical Biochemistry KB 3-01-1, Rigshospitalet, Copenhagen, Denmark
,
Tobias Gedde-Dahl
2   Medical Department A
,
Geir Tjønnfjord
2   Medical Department A
,
Bruno O. Villoutreix
3   INSERM U428, University of Paris V, School of Pharmacy, Paris, France
,
Frank Brosstad
4   Research Institute for Internal Medicine, Rikshospitalet Oslo, Norway
› Author Affiliations
Further Information

Publication History

Received 22 February 2002

Accepted after revision 26 June 2002

Publication Date:
09 December 2017 (online)

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Summry

Homozygosity for a novel D180G mutation in the protease domain of protein C, associated with plasma protein C activity and antigen levels of 8% of normal was identified in a thrombosis prone family. Transient expression of protein C in HK-293 cells and analysis of protein C antigen in culture media and cell lysates showed that the secretion of mutant protein as compared with wild-type protein was reduced by 79% while the intracellular contents were similar. Computer analysis of the X-ray structure of activated protein C and of a theoretical model of the zymogen predicts that the mutation destabilises the molecule locally. Our results are compatible with a relatively unstable mutant molecule that could be trapped inside the cell and degraded. However, if secreted the mutant molecule could have a relatively normal catalytic activity and structure consistent with the plasma levels of protein C activity and the late onset of thrombosis.

Keywords

Protein C deficiency - mutation - venous thrombosis - skin necrosis - serine proteinase
 

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