title: Fatal hemorrhage in mice lacking gamma-glutamyl carboxylase.
abstract: The carboxylation of glutamic acid residues to gamma-carboxyglutamic acid (Gla) by the vitamin K-dependent gamma-glutamyl carboxylase (gamma-carboxylase) is an essential posttranslational modification required for the biological activity of a number of proteins, including proteins involved in blood coagulation and its regulation. Heterozygous mice carrying a null mutation at the gamma-carboxylase (Ggcx) gene exhibit normal development and survival with no evidence of hemorrhage and normal functional activity of the vitamin K-dependent clotting factors IX, X, and prothrombin. Analysis of a Ggcx(+/-) intercross revealed a partial developmental block with only 50% of expected Ggcx(-/-) offspring surviving to term, with the latter animals dying uniformly at birth of massive intra-abdominal hemorrhage. This phenotype closely resembles the partial midembryonic loss and postnatal hemorrhage previously reported for both prothrombin- and factor V (F5)-deficient mice. These data exclude the existence of a redundant carboxylase pathway and suggest that functionally critical substrates for gamma-carboxylation, at least in the developing embryo and neonate, are primarily restricted to components of the blood coagulation cascade.
authors.affiliation: Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhu
authors.forename: Hongmin
authors.initials: H
authors.lastname: Sun
authors.forename: Richard M
authors.initials: RM
authors.lastname: Raymond
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Furie
authors.forename: Bruce
authors.initials: B
authors.lastname: Furie
authors.forename: Mila
authors.initials: M
authors.lastname: Bronstein
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: Randal
authors.initials: R
authors.lastname: Westrick
authors.forename: David
authors.initials: D
authors.lastname: Ginsburg
mesh_terms: D000005:Abdomen / Q000473:pathology; D000818:Animals; D001779:Blood Coagulation Factors / Q000378:metabolism; D019735:Carbon-Carbon Ligases / Q000172:deficiency* / Q000378:metabolism; D006470:Hemorrhage / Q000201:enzymology / Q000209:etiology*; D051379:Mice; D008817:Mice, Mutant Strains; D010641:Phenotype; D015996:Survival Rate
chemical_list: D001779:Blood Coagulation Factors; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase