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.
Zhu
Aihua
A
Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Sun
Hongmin
H
Raymond
Richard M
RM
Furie
Barbara C
BC
Furie
Bruce
B
Bronstein
Mila
M
Kaufman
Randal J
RJ
Westrick
Randal
R
Ginsburg
David
D
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
D001779:Blood Coagulation Factors; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase