VKORC1 deficiency in mice causes early postnatal lethality due to severe bleeding

Gabriele Spohn; Andre Kleinridders; F. Thomas Wunderlich; Matthias Watzka; Frank Zaucke; Katrin Blum-bach; Christof Geisen; Erhard Seifried; Clemens Müller; Mats Paulsson; Jens C. Brüning; Johannes Oldenburg

doi:10.1160/TH09-03-0204

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2009; 101(06): 1044-1050
DOI: 10.1160/TH09-03-0204

Rapid and Short Communication

Schattauer GmbH

VKORC1 deficiency in mice causes early postnatal lethality due to severe bleeding

Autoren

Gabriele Spohn

¹Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Germany

²Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Center of Molecular Medicine Cologne (CMMC), University of Cologne, and 2nd Department for Internal Medicine, University Hospital Cologne, and Max Planck Institute for the Biology of Ageing, Cologne, Germany

³Institute of Transfusion Medicine and Immunohaematology, DRK Blood Donor Service Baden-Württemberg-Hessen, Frankfurt/Main, Germany
Andre Kleinridders

²Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Center of Molecular Medicine Cologne (CMMC), University of Cologne, and 2nd Department for Internal Medicine, University Hospital Cologne, and Max Planck Institute for the Biology of Ageing, Cologne, Germany
F. Thomas Wunderlich

²Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Center of Molecular Medicine Cologne (CMMC), University of Cologne, and 2nd Department for Internal Medicine, University Hospital Cologne, and Max Planck Institute for the Biology of Ageing, Cologne, Germany
Matthias Watzka

¹Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Germany
Frank Zaucke

⁴Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
Katrin Blum-bach

⁴Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
Christof Geisen

³Institute of Transfusion Medicine and Immunohaematology, DRK Blood Donor Service Baden-Württemberg-Hessen, Frankfurt/Main, Germany
Erhard Seifried

³Institute of Transfusion Medicine and Immunohaematology, DRK Blood Donor Service Baden-Württemberg-Hessen, Frankfurt/Main, Germany
Clemens Müller

⁵Institute of Human Genetics, University of Würzburg, Würzburg, Germany
Mats Paulsson

⁴Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
Jens C. Brüning

²Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Center of Molecular Medicine Cologne (CMMC), University of Cologne, and 2nd Department for Internal Medicine, University Hospital Cologne, and Max Planck Institute for the Biology of Ageing, Cologne, Germany
Johannes Oldenburg

¹Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Germany

Abstract

Summary

Vitamin K hydroquinone is oxidised to the epoxide form (K>O) during vitamin K-dependent posttranslational γ-glutamyl carboxylation resulting in biological active so called vitamin K-dependent proteins. In turn, K>O is reduced by the enzyme VKORC1 (vitamin K epoxide reductase complex component 1) to complete the vitamin K cycle. To investigate the biological role of VKORC1 in vivo, we generated VKORC1 knockout mice. Homozygous VKORC1-deficient mice developed normally until birth. Within 2–20 days after birth, the knockout mice died due to extensive, predominantly intracerebral haemorrhage. Bleeding resulted from a severe deficiency of γ-carboxylated clotting factors. This lethal phenotype could be rescued by oral administration of vitamin K. Additionally, morphometric analysis of the limbs in VKORC1-deficient animals revealed reduced length of bone calcification relative to wild-type control mice. The observed phenotype of VKORC1 knockout mice excludes the existence of other enzymes with VKOR activity that can substitute to supply vitamin K hydroquinone required for maturation of blood clotting factors. Thus, our study underscores the essential role of VKORC1 in vitamin K-dependent γ-glutamyl carboxylation.

Keywords

VKORC1 - knockout mouse - bleeding phenotype - bone pheno-type - vitamin K

Volltext

Referenzen

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