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

Yuan Yan Sin, Laurel L. Ballantyne, Kamalika Mukherjee, Tim St Amand, Lianna Kyriakopoulou, Andreas Schulze, Colin D. Funk

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 CreERT2 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.

Original languageEnglish (US)
Article numbere80001
JournalPloS one
Volume8
Issue number11
DOIs
StatePublished - Nov 4 2013

Fingerprint

Hyperargininemia
Arginase
arginase
amino acid metabolism
Metabolism
Amino Acids
mice
Hyperammonemia
Liver
amino acids
animal models
tamoxifen
citrulline
Branched Chain Amino Acids
Citrulline
Gene Knockout Techniques
liver
branched chain amino acids
Ornithine
ornithine

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Sin, Y. Y., Ballantyne, L. L., Mukherjee, K., St Amand, T., Kyriakopoulou, L., Schulze, A., & Funk, C. D. (2013). Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism. PloS one, 8(11), [e80001]. https://doi.org/10.1371/journal.pone.0080001

Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism. / Sin, Yuan Yan; Ballantyne, Laurel L.; Mukherjee, Kamalika; St Amand, Tim; Kyriakopoulou, Lianna; Schulze, Andreas; Funk, Colin D.

In: PloS one, Vol. 8, No. 11, e80001, 04.11.2013.

Research output: Contribution to journalArticle

Sin, YY, Ballantyne, LL, Mukherjee, K, St Amand, T, Kyriakopoulou, L, Schulze, A & Funk, CD 2013, 'Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism', PloS one, vol. 8, no. 11, e80001. https://doi.org/10.1371/journal.pone.0080001
Sin YY, Ballantyne LL, Mukherjee K, St Amand T, Kyriakopoulou L, Schulze A et al. Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism. PloS one. 2013 Nov 4;8(11). e80001. https://doi.org/10.1371/journal.pone.0080001
Sin, Yuan Yan ; Ballantyne, Laurel L. ; Mukherjee, Kamalika ; St Amand, Tim ; Kyriakopoulou, Lianna ; Schulze, Andreas ; Funk, Colin D. / Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism. In: PloS one. 2013 ; Vol. 8, No. 11.
@article{aa60e322102b42b89dac9942d2460f1a,
title = "Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism",
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 CreERT2 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.",
author = "Sin, {Yuan Yan} and Ballantyne, {Laurel L.} and Kamalika Mukherjee and {St Amand}, Tim and Lianna Kyriakopoulou and Andreas Schulze and Funk, {Colin D.}",
year = "2013",
month = "11",
day = "4",
doi = "10.1371/journal.pone.0080001",
language = "English (US)",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "11",

}

TY - JOUR

T1 - Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism

AU - Sin, Yuan Yan

AU - Ballantyne, Laurel L.

AU - Mukherjee, Kamalika

AU - St Amand, Tim

AU - Kyriakopoulou, Lianna

AU - Schulze, Andreas

AU - Funk, Colin D.

PY - 2013/11/4

Y1 - 2013/11/4

N2 - 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 CreERT2 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.

AB - 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 CreERT2 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.

UR - http://www.scopus.com/inward/record.url?scp=84891875024&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84891875024&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0080001

DO - 10.1371/journal.pone.0080001

M3 - Article

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 11

M1 - e80001

ER -