Premium
Hyperargininemia in an inducible arginase‐1 deficient mouse model
Author(s) -
Sin Angie,
Ballantyne Laurel L,
Mukherjee Kamalika,
St. Amand Tim,
McCracken Crystal,
Levandovskiy Valeriy,
Schulze Andreas,
Funk Colin D
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1009.3
Subject(s) - arginase , ornithine , knockout mouse , arginine , protein arginine methyltransferase 5 , endocrinology , medicine , conditional gene knockout , chemistry , biology , phenotype , biochemistry , gene , amino acid , methyltransferase , methylation
We generated an inducible arginase‐1 (Arg1) deficient mouse model by crossing “floxed” Arg1 mice with the Cre‐ER‐T2 model (Arg1‐Cre). These Arg1‐Cre mice die about 2 weeks after tamoxifen administration regardless of the starting age of inducing the knockout and show signs of hyperammonemia and significantly elevated arginine levels (n=4–5; four time points from 2 weeks to 14 weeks of age). Plasma creatine and creatinine levels are normal but guanidinoacetate is increased as assessed by tandem mass spectrometry. Attempts to rescue the lethality or at least to mitigate the biochemical defects caused by loss of arginase‐1 by supplementation of ornithine in the drinking water (n=5) were unsuccessful. An arginase‐1/green fluorescent protein retains full catalytic activity and is being introduced into liver hepatocytes and induced pluripotent stem cells obtained from Arg1‐Cre mice in vitro and to animals in vivo to restore normal biochemistry and to rescue the severe phenotypic consequences of deficiency of this enzyme. Arg1‐Cre mice should prove useful to explore the biochemical defects associated with arginase‐1 deficiency and to explore genetic correction strategies.