RGD Reference Report - Conditional disruption of hepatic carbamoyl phosphate synthetase 1 in mice results in hyperammonemia without orotic aciduria and can be corrected by liver-directed gene therapy.

General

Conditional disruption of hepatic carbamoyl phosphate synthetase 1 in mice results in hyperammonemia without orotic aciduria and can be corrected by liver-directed gene therapy.
Authors:	Khoja, Suhail Nitzahn, Matt Hermann, Kip Truong, Brian Borzone, Roberta Willis, Brandon Rudd, Mitchell Palmer, Donna J Ng, Philip Brunetti-Pierri, Nicola Lipshutz, Gerald S
Citation:	Khoja S, etal., Mol Genet Metab. 2018 Apr 12. pii: S1096-7192(18)30059-3. doi: 10.1016/j.ymgme.2018.04.001.
RGD ID:	13628400
Pubmed:	PMID:29801986 (View Abstract at PubMed)
PMCID:	PMC6076338 (View Article at PubMed Central)
DOI:	DOI:10.1016/j.ymgme.2018.04.001 (Journal Full-text)
Carbamoyl phosphate synthetase 1 (CPS1) is a urea cycle enzyme that forms carbamoyl phosphate from bicarbonate, ammonia and ATP. Bi-allelic mutations of the CPS1 gene result in a urea cycle disorder presenting with hyperammonemia, often with reduced citrulline, and without orotic aciduria. CPS1 deficiency is particularly challenging to treat and lack of early recognition typically results in early neonatal death. Therapeutic interventions have limited efficacy and most patients develop long-term neurologic sequelae. Using transgenic techniques, we generated a conditional Cps1 knockout mouse. By loxP/Cre recombinase technology, deletion of the Cps1 locus was achieved in adult transgenic animals using a Cre recombinase-expressing adeno-associated viral vector. Within four weeks from vector injection, all animals developed hyperammonemia without orotic aciduria and died. Minimal CPS1 protein was detectable in livers. To investigate the efficacy of gene therapy for CPS deficiency following knock-down of hepatic endogenous CPS1 expression, we injected these mice with a helper-dependent adenoviral vector (HDAd) expressing the large murine CPS1 cDNA under control of the phosphoenolpyruvate carboxykinase promoter. Liver-directed HDAd-mediated gene therapy resulted in survival, normalization of plasma ammonia and glutamine, and 13% of normal Cps1 expression. A gender difference in survival suggests that female mice may require higher hepatic CPS1 expression. We conclude that this conditional murine model recapitulates the clinical and biochemical phenotype detected in human patients with CPS1 deficiency and will be useful to investigate ammonia-mediated neurotoxicity and for the development of cell- and gene-based therapeutic approaches.

RGD Manual Disease Annotations Click to see Annotation Detail View

Only show annotations with direct experimental evidence (0 objects hidden)

Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
CARBONIC ANHYDRASE VA DEFICIENCY, HYPERAMMONEMIA DUE TO	treatment	ISO	Cps1 (Mus musculus)	13628400; 13628400		RGD
CARBONIC ANHYDRASE VA DEFICIENCY, HYPERAMMONEMIA DUE TO	treatment	IMP		13628400		RGD

Objects Annotated

Genes (Rattus norvegicus)

Cps1 (carbamoyl-phosphate synthase 1)

Genes (Mus musculus)

Cps1 (carbamoyl-phosphate synthetase 1)

Genes (Homo sapiens)

CPS1 (carbamoyl-phosphate synthase 1)

Additional Information

Gene Annotator (Functional Annotation) unavailable	Gene Annotator (Annotation Distribution) unavailable	Variant Visualizer (Genomic Variants) unavailble Variant Visualizer (Genomic Variants) unavailable
Gene Annotator (Functional Annotation)	Gene Annotator (Annotation Distribution)	Variant Visualizer (Genomic Variants)

InterViewer (Protein-Protein Interactions) unavailable	Gviewer (Genome Viewer) unavailable	Variant Visualizer (Damaging Variants) unavailble Variant Visualizer (Damaging Variants) unavailable
InterViewer (Protein-Protein Interactions)	GViewer (Genome Viewer)	Variant Visualizer (Damaging Variants)

Gene Annotator (Annotation Comparison) unavailable	OLGA (Gene List Generator) unavailable
Gene Annotator (Annotation Comparison)	OLGA (Gene List Generator)	Excel (Download)

MOET (Multi-Ontology Enrichement) unavailable	GOLF (Gene-Ortholog Location Finder) unavailable
MOET (Multi-Ontology Enrichement)	GOLF (Gene-Ortholog Location Finder)

Create Name:

Description:

Send us a Message

Conditional disruption of hepatic carbamoyl phosphate synthetase 1 in mice results in hyperammonemia without orotic aciduria and can be corrected by liver-directed gene therapy.