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Cerebral tissue was collected in 8-week-old spf-j and WT and snap frozen until analysis. With the plasma amino acid profile suggesting perturbations in the biochemical phenotype at baseline, we next tried to provoke hyperammonemia and orotic aciduria. Spf-J and WT littermates were maintained on a high protein diet for 2 weeks Figs.
At the end of 2 weeks the animals were bled retro-orbitally and plasma ammonia and orotate were determined. Although we were not able to increase plasma ammonia significantly in spf-J , plasma orotate increased 2. Therefore, spf-J , while displaying mild plasma biochemical abnormalities at baseline, may be provoked by protein challenge to display one of the biochemical hallmarks of OTCD, orotate accumulation. C Plasma ammonia. D Liver transaminases. Patients with urea cycle disorders may experience episodes of metabolic instability termed acute metabolic decompensation.
To simulate viral infection with a systemic inflammatory response in spf-j mice, intraperitoneal poly I:C was given once a day for 3 days [ 23 ].
Following injection with poly I:C, spf-j mice fail to show differences in plasma ammonia Fig. To explore amino acid perturbations, plasma, liver and cerebral amino acids were measured. Heat maps were constructed showing the change from baseline for each tissue Fig. In plasma, there was a similar general decrease in amino acids from baseline in both spf-j and WT Fig. Similar to plasma, most of the changes from baseline in liver were not statistically different Fig.
Unlike plasma and liver, the effect of poly I:C treatment in the brain was more pronounced Fig. Heat maps were constructed as described in Methods to represent the change in amino acid concentrations from baseline for plasma left panel , liver middle panel and cerebrum right panel. Due to the inheritance of OTCD, the phenotypic expression of the disease severity in patients is dependent upon the nature of the mutation, genetic background and in females, X-inactivation in the liver.
In males, this disorder classically manifests with symptomatic hyperammonemia in infancy, although milder alleles have been described [ 12 , 13 , 19 ]. In addition, phenotypic variability can be seen in males within the same family with the same mutation suggesting modifier alleles may play a role [ 24 ].
Galloway et al. The precipitant of this episode was unknown.
This amino acid substitution in the OTC enzyme is identical to the mutation described here in the spf-J mouse Fig. The mutation lies outside the substrate binding and catalytic regions of the enzyme [ 13 ] and may be related to homo-oligomerization or stability of the enzyme. These findings lead us to suggest that the K80N mutation may destabilize the enzyme, leading to its early degradation. In general, mouse models of UCD have yielded insights into disease pathophysiology, the influence of genetic background and the evaluation of novel therapeutics.
Two animal models of OTCD, the sparse-fur spf and the sparse-fur abnormal skin and hair spf-ash , have been used to study disease pathogenesis and to evaluate therapies reviewed in [ 21 ]. The biochemical characteristics of both of these models include OTCD, elevated plasma ammonia and glutamine, low plasma citrulline and arginine, and elevated urinary orotic acid excretion. In contrast to these previously described models, the spf-J displays a milder phenotype: normal ammonia and plasma orotate at baseline Figs.
The elevated plasma glutamine seen in spf-J at baseline Table 1 suggests that ammonia disposal is indeed compromised and that glutamine synthetase may provide an alternative route of elimination. Consistent with this assertion is the depletion of plasma branched chain amino acids, which may be consumed to support glutamine synthesis reviewed in [ 27 ]. Patients with urea cycle disorders experience episodes of acute metabolic decompensation characterized by hyperammonemia.
Viral infection is the most common cause of acute metabolic decompensation and is associated with markers of increased morbidity [ 28 ].
The viral infection mimic, poly I:C was not sufficient to produce hyperammonemia consistently in spf-j Fig. However, tissue amino acid perturbations could be seen. Although both WT and spf-j displayed similar trends in plasma amino acids Fig. These findings, combined with the elevation of cerebral amino acids at baseline Table 3 , supports the hypothesis of altered cerebral amino acid metabolism or transport in spf-j. In the brain, amino acids and their derivatives play a role in synaptic transmission by serving as a source of energy, precursors to neuro-active compounds, allosteric regulators, and even neurotransmitters [ 29 , 30 ].
Several amino acids involved in various aspects of neurotransmission failed to increase or were depressed in spf-j including glycine excitatory and inhibitory neurotransmission , histidine source of histamine and arginine source of nitric oxide.
These perturbations in the cerebral amino acid pool may be due to decreased transport across the blood brain barrier, depressed synthesis, or increased metabolism [ 31 ]. Being that many amino acids are precursors or cofactors for neurotransmission, one could postulate that these perturbations in cerebral amino acids may lead to neurocognitive deficits.
Indeed, alterations in cognitive functioning seen in asymptomatic OTC carriers suggest that other factors besides hyperammonemia may play a role [ 32 ]. This avenue of inquiry should be explored and necessitates defining the neurocognitive phenotype of spf-j and the relationship between systemic inflammation and brain amino acid metabolism. In conclusion, the spf—J has the benefits of a pure inbred strain, allowing for the ideal characterization of this mild OTC mutation on a uniform genetic background. Added benefits include fecundity and long-term survival. Due to the robust nature of these animals, this model is ideal for studying interactions with other metabolic pathways and mapping of genes that modulate disease activity.
Regarding therapeutic approaches, the instability of the enzyme suggests that this model may serve as a target for the preclinical evaluation of small molecule chaperones or activators. From a pathophysiologic standpoint, we anticipate that this model may also be useful for studying cerebral amino acid metabolism and transport and the long-term effects of mild OTCD on neurodevelopment and IQ. Among the many human mutations that lead to a pathological condition, few have a spontaneous orthologous equivalent in the mouse and vice versa. In this regard, the spf-J mouse is a unique tool for studying mild OTC deficiency.
Work performed by T. Work performed by H. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Center for Biotechnology Information , U. PLoS One. Published online Feb 3. Tatyana N. Tarasenko , 1 Odrick R.