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: Aihua Zhu, Hongmin Sun, Richard M Raymond Jr, Barbara C Furie, Bruce Furie, Mila Bronstein, Randal J Kaufman, Randal Westrick, David Ginsburg
• Journal: Blood (Blood) Vol. 109 Issue 12 Pg. 5270-5 (Jun 15 2007) ISSN: 0006-4971 [Print] United States
• PMID: 17327402 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Coagulation Factors
• Carbon-Carbon Ligases
• glutamyl carboxylase

Topics

• Abdomen (pathology)
• Animals
• Blood Coagulation Factors (metabolism)
• Carbon-Carbon Ligases (deficiency, metabolism)
• Hemorrhage (enzymology, etiology)
• Mice
• Mice, Mutant Strains
• Phenotype
• Survival Rate