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Comprehensive characterization of ureagenesis in the spf ash mouse, a model of human ornithine transcarbamylase deficiency, reveals age‐dependency of ammonia detoxification
Author(s) -
Allegri Gabriella,
Deplazes Sereina,
Rimann Nicole,
Causton Benjamin,
Scherer Tanja,
Leff Jonathan W.,
DiezFernandez Carmen,
Klimovskaia Anna,
Fingerhut Ralph,
Krijt Jakub,
Kožich Viktor,
Nuoffer JeanMarc,
GrischChan Hiu M.,
Thöny Beat,
Häberle Johannes
Publication year - 2019
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12068
Subject(s) - hyperammonemia , ornithine transcarbamylase , urea cycle , detoxification (alternative medicine) , orotic acid , ornithine transcarbamylase deficiency , enzyme , glutamine , biochemistry , catabolism , ornithine , biology , metabolism , arginine , medicine , endocrinology , amino acid , pathology , alternative medicine
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.