Phenotypic Characterization of Ggt1dwg/dwg Mice, a Mouse Model for Hereditary gamma-Glutamyl Transferase Deficiency

摘要

Ggt1(dwg/dwg) mice are spontaneous mutant mice with a nucleotide deletion in the Ggt1 gene. They are characterized by dwarfism, cataract, and coat color abnormality. These abnormalities in the external appearance of Ggt1(dwg/dwg) mice closely resemble those of previously reported GGT1-deficient mice, Ggt1(tm1Zuk/tm1Zuk) (Ggt1(-/-)) and Ggt1(enu1/enu1), generated by gene targeting or ENU mutagenesis. However, whether the pathological features of Ggt1(dwg/dwg) mice are also similar to those of the Ggt1(-/-) and Ggt1(enu1/enu1) mice remains unclear. To clarify the pathogenesis of Ggt1(dwg/dwg) mice, we physiologically and histologically investigated the abnormalities of Ggt1(dwg/dwg) mice in this study. First, we analyzed the activity of GGT1 and GSH levels in Ggt1(dwg/dwg) mice. GGT1 activity in the Ggt1(dwg/dwg) mice was reduced to approximately 4.0 of that in the wild-type mice. Plasma and kidney GSH levels were markedly increased, while eye and liver GSH levels were markedly decreased, in the Ggt1(dwg/dwg) mice. Notably, no significant difference in survival rate was observed between the Ggt1(dwg/dwg) and wild-type mice, whereas high mortality was reported in the Ggt1(-/-) and Ggt1(enu1/enu1) mice. Growth retardation, degeneration of lens fibers, and an increased number of osteoclasts in the Ggt1(dwg/dwg) mice were reversed by administration of N-acetyl-L-cysteine, a precursor of GSH synthesis. Thus, we conclude that the abnormalities of Ggt1(dwg/dwg) mice are caused by alteration of the GSH levels due to the depression of GGT1 activity and that Ggt1(dwg/dwg) mice will be a useful model for GGT deficiency with peculiar features.