Fatal hemorrhage in mice lacking gamma-glutamyl carboxylase.
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.
T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T2 T3 T4 T5 T6 T7 T8 T9
GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-N GENE-Y
gamma-carboxylase Ggcx vitamin K-dependent clotting factors IX, X prothrombin Ggcx Ggcx vitamin K-dependent gamma-glutamyl carboxylase prothrombin factor V F5 gamma-glutamyl gamma-glutamyl carboxylase glutamic acid gamma-carboxyglutamic acid vitamin K Gla vitamin K gamma-glutamyl carboxylase gamma-carboxylase