title: VKORC1 deficiency in mice causes early postnatal lethality due to severe bleeding.
abstract: 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.
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Spohn
authors.forename: Andre
authors.initials: A
authors.lastname: Kleinridders
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.forename: Matthias
authors.initials: M
authors.lastname: Watzka
authors.forename: Frank
authors.initials: F
authors.lastname: Zaucke
authors.forename: Katrin
authors.initials: K
authors.lastname: Blumbach
authors.forename: Christof
authors.initials: C
authors.lastname: Geisen
authors.forename: Erhard
authors.initials: E
authors.lastname: Seifried
authors.forename: Clemens
authors.initials: C
authors.lastname: Müller
authors.forename: Mats
authors.initials: M
authors.lastname: Paulsson
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000097:blood / Q000254:growth & development / Q000502:physiology*; D001779:Blood Coagulation Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001842:Bone and Bones / Q000201:enzymology / Q000473:pathology; D002113:Calcification, Physiologic; D002245:Carbon Dioxide / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000235:genetics; D053595:Embryonic Stem Cells / Q000201:enzymology / Q000473:pathology; D005121:Extremities / Q000254:growth & development; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D014812:Vitamin K / Q000737:chemistry / Q000378:metabolism*; D064417:Vitamin K Epoxide Reductases
chemical_list: D001779:Blood Coagulation Factors; D014812:Vitamin K; D002245:Carbon Dioxide; C041069:carboxyl radical; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases