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

نویسندگان

  • Gabriele Spohn
  • Andre Kleinridders
  • F Thomas Wunderlich
  • Matthias Watzka
  • Frank Zaucke
  • Katrin Blumbach
  • Christof Geisen
  • Erhard Seifried
  • Clemens Müller
  • Mats Paulsson
  • Jens C Brüning
  • Johannes Oldenburg
چکیده

Vitamin K hydroquinone is oxidised to the epoxide form (K>O) during vitamin K-dependent posttranslational gamma-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 gamma-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 gamma-glutamyl carboxylation.

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عنوان ژورنال:
  • Thrombosis and haemostasis

دوره 101 6  شماره 

صفحات  -

تاریخ انتشار 2009