A hypomorphic model of CPS1 deficiency for investigating the effects of hyperammonemia on the developing nervous system
Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a rare metabolic disorder that, in neonatal onset, is typically characterized by severe life-threatening and neurologically injuring hyperammonemic episodes with high unmet patient need. Patients that retain limited enzyme activity may present later in life with less severe hyperammonemia. CPS1 drives the first step in the urea cycle, the pathway terrestrial mammals utilize to metabolize nitrogen. In order to probe the effect of hyperammonemia on the developing nervous system and explore new therapies, a murine Cps1 exon 3-4 mutant was previously generated. However, these mice die within 24 h of birth, limiting study capabilities. Herein, we developed a novel Cps1 hypomorphic murine model with residual enzyme activity that maintains survival, but with dysfunction of Cps1 that could be detected biochemically. Characterization, based on the orthologous human variant Asn674Ile, revealed that the variant is reproducible, 100% penetrant and biochemically phenocopies the human disorder. The hypomorph presents with elevated ammonia and glutamate, and reduced citrulline, and with an impaired rate of ureagenesis, providing a novel platform to study and develop therapies for CPS1 deficiency.
Authors
- Gerald S. Lipshutz (ORCID: https://orcid.org/0000-0001-7876-6776)
- Irina Zhuravka
- Michelle Tang (ORCID: https://orcid.org/0000-0002-8779-8697)
- Georgios Makris (ORCID: https://orcid.org/0000-0001-9097-1991)
- Qin Sun (ORCID: https://orcid.org/0000-0002-8270-3943)
- Guoyao Wu (ORCID: https://orcid.org/0000-0001-8058-6969)
- Lindsay M. Lueptow (ORCID: https://orcid.org/0000-0001-5343-7618)
- Johannes Häberle (ORCID: https://orcid.org/0000-0003-0635-091X)
- Gareth A. Cromie (ORCID: https://orcid.org/0000-0001-5265-1970)
- Martin Poms (ORCID: https://orcid.org/0000-0002-4426-314X)
- Aimée M. Dudley (ORCID: https://orcid.org/0000-0003-3644-0625)
- Taryn Diep
- Rachel C. Reyes (ORCID: https://orcid.org/0000-0002-4546-420X)
- Stuti Bakshi
- Brandon Willis
- Isabel L Day
Institutions
- Pacific Northwest Diabetes Research Institute (US)
- University of California, Los Angeles (US)
- Baylor College of Medicine (US)
- UCLA Health (US)
- University Children's Hospital Zurich (CH)
- Olive View-UCLA Medical Center (US)
- Baylor Genetics (US)
- University of California, Davis (US)
Publication Details
- Journal
- Disease Models & Mechanisms
- Published
- 2025-05-27
- DOI
- https://doi.org/10.1242/dmm.052303
- Primary Topic
- Metabolism and Genetic Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- University of California, Davis
- National Institute of Neurological Disorders and Stroke
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development