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

Abstract

Abstract: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.

N-acetyl-cysteine prevents age-related hearing loss and the progressive loss of inner hair cells in γ-glutamyl transferase 1 deficient mice

“…The dwarf gray ( dwg ) mutation is a spontaneous 13 bp deletion in exon 7 of the Ggt1 gene, which causes a frameshift and premature stop codon [ 20 ]. Consistent with previous reports, dwg / dwg mice [ 21 , 24 ], like mice homozygous for the targeted Ggt1 tm1Zuk [ 25 – 28 ] and mice homozygous for the ENU-induced Ggt1 enu1 [ 29 , 30 ], exhibit dwarfism, skeletal abnormalities, diluted pigmentation, cataracts, and reduced fertility. The mutations differ, however, in the effects they have on life span.…”

“…Consistent with our prediction, dwg/dwg mice developed ARHL; however, the hearing loss was unexpectedly associated with a highly selective loss of IHC, an unusual and extremely rare type of cochlear pathology. Since dwg/dwg mutants are deficient in intracellular GSH [ 21 ] and susceptible to oxidative stress, we hypothesized that n-acetyl-L-cysteine (NAC), which promotes the de novo synthesis of GSH [ 22 , 23 ], would prevent ARHL and IHC loss while receiving treatment, but that ARHL and hair cell loss would reappear when NAC treatment was discontinued.…”

Serum Metabolic Profiling Reveals the Antidepressive Effects of the Total Iridoids of Valeriana jatamansi Jones on Chronic Unpredictable Mild Stress Mice

“…In addition, glutamine and glutamate can be interconnected through enzyme catalysis, and they are both precursors of glutathione (GSH). As GGT (Yamada et al, 2013) activity decreases, this may influence GSH metabolism. GSH concentrations in the blood serum, plasma, or the brain have also been identified to be significantly decreased in depression (de Souza et al, 2006;Kodydkova et al, 2009;Maes et al, 2011).…”

Gamma-Glutamyl Transpeptidase

“…H. Hanigan & Frierson, 1996). The development of strains of GGT-knockout mice revealed the role of GGT in the distribution of cysteine throughout the body (Harding et al, 1997; Lieberman et al, 1996; Yamada, Tsuji, & Kunieda, 2013). GGT-knockout mice excrete 2500-fold more GSH in their urine than wild-type mice (Lieberman, et al, 1996).…”