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Comprehensive characterization of ureagenesis in the spfash mouse, a model of human ornithine transcarbamylase deficiency, reveals age-dependency of ammonia detoxification
G. Allegri, S. Deplazes, N. Rimann, B. Causton, T. Scherer, JW. Leff, C. Diez-Fernandez, A. Klimovskaia, R. Fingerhut, J. Krijt, V. Kožich, JM. Nuoffer, HM. Grisch-Chan, B. Thöny, J. Häberle,
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't, Review
PubMed
30714172
DOI
10.1002/jimd.12068
Knihovny.cz E-resources
- MeSH
- Ammonia metabolism MeSH
- Hyperammonemia genetics metabolism pathology MeSH
- Liver metabolism pathology MeSH
- Humans MeSH
- Urea metabolism MeSH
- Disease Models, Animal MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- Ornithine Carbamoyltransferase Deficiency Disease genetics metabolism pathology MeSH
- Ornithine Carbamoyltransferase genetics MeSH
- Aging physiology MeSH
- Age Factors MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
The most common ureagenesis defect is X-linked ornithine transcarbamylase (OTC) deficiency which is a main target for novel therapeutic interventions. The spf ash mouse model carries a variant (c.386G>A, p.Arg129His) that is also found in patients. Male spf ash mice have a mild biochemical phenotype with low OTC activity (5%-10% of wild-type), resulting in elevated urinary orotic acid but no hyperammonemia. We recently established a dried blood spot method for in vivo quantification of ureagenesis by Gas chromatography-mass spectrometry (GC-MS) using stable isotopes. Here, we applied this assay to wild-type and spf ash mice to assess ureagenesis at different ages. Unexpectedly, we found an age-dependency with a higher capacity for ammonia detoxification in young mice after weaning. A parallel pattern was observed for carbamoylphosphate synthetase 1 and OTC enzyme expression and activities, which may act as pacemaker of this ammonia detoxification pathway. Moreover, high ureagenesis in younger mice was accompanied by elevated periportal expression of hepatic glutamine synthetase, another main enzyme required for ammonia detoxification. These observations led us to perform a more extensive analysis of the spf ash mouse in comparison to the wild-type, including characterization of the corresponding metabolites, enzyme activities in the liver and plasma and the gut microbiota. In conclusion, the comprehensive enzymatic and metabolic analysis of ureagenesis performed in the presented depth was only possible in animals. Our findings suggest such analyses being essential when using the mouse as a model and revealed age-dependent activity of ammonia detoxification.
Department of Clinical Chemistry Inselspital Bern Bern Switzerland
Institute for Molecular Systems Biology ETH Zurich Zurich Switzerland
Kaleido Biosciences Inc Lexington Massachusetts
Swiss Newborn Screening Laboratory University Children's Hospital Zurich Switzerland
References provided by Crossref.org
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- $a The most common ureagenesis defect is X-linked ornithine transcarbamylase (OTC) deficiency which is a main target for novel therapeutic interventions. The spf ash mouse model carries a variant (c.386G>A, p.Arg129His) that is also found in patients. Male spf ash mice have a mild biochemical phenotype with low OTC activity (5%-10% of wild-type), resulting in elevated urinary orotic acid but no hyperammonemia. We recently established a dried blood spot method for in vivo quantification of ureagenesis by Gas chromatography-mass spectrometry (GC-MS) using stable isotopes. Here, we applied this assay to wild-type and spf ash mice to assess ureagenesis at different ages. Unexpectedly, we found an age-dependency with a higher capacity for ammonia detoxification in young mice after weaning. A parallel pattern was observed for carbamoylphosphate synthetase 1 and OTC enzyme expression and activities, which may act as pacemaker of this ammonia detoxification pathway. Moreover, high ureagenesis in younger mice was accompanied by elevated periportal expression of hepatic glutamine synthetase, another main enzyme required for ammonia detoxification. These observations led us to perform a more extensive analysis of the spf ash mouse in comparison to the wild-type, including characterization of the corresponding metabolites, enzyme activities in the liver and plasma and the gut microbiota. In conclusion, the comprehensive enzymatic and metabolic analysis of ureagenesis performed in the presented depth was only possible in animals. Our findings suggest such analyses being essential when using the mouse as a model and revealed age-dependent activity of ammonia detoxification.
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