Phenotypic Characterization of Ggt1^dwg/dwg Mice,a Mouse Model for Hereditary γ-GlutamylTransferase Deficiency

抄録

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.