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Title: Alanine-glyoxylate aminotransferase-deficient mice, a model for primary hyperoxaluria that responds to adenoviral gene transfer
Authors: Salido, Eduardo C.
Li, Xiao M.
Lu, Yang
Wang, Xia
Santana, Alfredo 
Roy-Chowdhury, Namita
Torres, Armando
Shapiro, Larry J.
Roy-Chowdhury, Jayanta
UNESCO Clasification: 32 Ciencias médicas
3205 Medicina interna
Keywords: Gene therapy
Knockout mouse
Issue Date: 2006
Journal: Proceedings of the National Academy of Sciences of the United States of America 
Abstract: Mutations in the alanine-glyoxylate amino transferase gene (AGXT) are responsible for primary hyperoxaluria type I, a rare disease characterized by excessive hepatic oxalate production that leads to renal failure. We generated a null mutant mouse by targeted mutagenesis of the homologous gene, Agxt, in embryonic stem cells. Mutant mice developed normally, and they exhibited hyperoxaluria and crystalluria. Approximately half of the male mice in mixed genetic background developed calcium oxalate urinary stones. Severe nephrocalcinosis and renal failure developed after enhancement of oxalate production by ethylene glycol administration. Hepatic expression of human AGT1, the protein encoded by AGXT, by adenoviral vector-mediated gene transfer in Agxt(-/-) mice normalized urinary oxalate excretion and prevented oxalate crystalluria. Subcellular fractionation and immunofluorescence studies revealed that, as in the human liver, the expressed wild-type human AGT1 was predominantly localized in mouse hepatocellular peroxisomes, whereas the most common mutant form of AGT1 (G170R) was localized predominantly in the mitochondria.
ISSN: 0027-8424
DOI: 10.1073/pnas.0607218103
Source: Proceedings of the National Academy of Sciences of the United States of America [ISSN 0027-8424], v. 103, p. 18249-18254
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