Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism

Sin, Y. Y., Ballantyne, L. L., Mukherjee, K., St. Amand, T., Kyriakopoulou, L., Schulze, A. and Funk, C. D. (2013) Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism. PLoS ONE, 8(11), e80001. (doi: 10.1371/journal.pone.0080001) (PMID:24224027) (PMCID:PMC3817112)

Abstract

Arginase deficiency is a rare autosomal recessive disorder resulting from a loss of the liver arginase isoform, arginase 1 (ARG1), which is the final step in the urea cycle for detoxifying ammonia. ARG1 deficiency leads to hyperargininemia, characterized by progressive neurological impairment, persistent growth retardation and infrequent episodes of hyperammonemia. Using the Cre/loxP-directed conditional gene knockout system, we generated an inducible Arg1-deficient mouse model by crossing "floxed" Arg1 mice with CreER(T2) mice. The resulting mice (Arg-Cre) die about two weeks after tamoxifen administration regardless of the starting age of inducing the knockout. These treated mice were nearly devoid of Arg1 mRNA, protein and liver arginase activity, and exhibited symptoms of hyperammonemia. Plasma amino acid analysis revealed pronounced hyperargininemia and significant alterations in amino acid and guanidino compound metabolism, including increased citrulline and guanidinoacetic acid. Despite no alteration in ornithine levels, concentrations of other amino acids such as proline and the branched-chain amino acids were reduced. In summary, we have generated and characterized an inducible Arg1-deficient mouse model exhibiting several pathologic manifestations of hyperargininemia. This model should prove useful for exploring potential treatment options of ARG1 deficiency.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sin, Dr Angie
• Authors: Sin, Y. Y., Ballantyne, L. L., Mukherjee, K., St. Amand, T., Kyriakopoulou, L., Schulze, A., and Funk, C. D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Copyright Holders: Copyright © 2013 Sin et al.
• First Published: First published in PLoS ONE 8(5): e80001
• Publisher Policy: Reproduced under a Creative Commons License