Fatal hemorrhage in mice lacking γ-glutamyl carboxylase

Abstract

AbstractThe carboxylation of glutamic acid residues to γ-carboxyglutamic acid (Gla) by the vitamin K–dependent γ-glutamyl carboxylase (γ-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 γ-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 γ-carboxylation, at least in the developing embryo and neonate, are primarily restricted to components of the blood coagulation cascade.