Language
English
Publication Date
7-1-2025
Journal
Disease Models & Mechanisms
DOI
10.1242/dmm.052303
PMID
40421838
PMCID
PMC12208401
PubMedCentral® Posted Date
6-20-2025
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Animals, Hyperammonemia, Disease Models, Animal, Carbamoyl-Phosphate Synthase (Ammonia), Nervous System, Humans, Mice, Carbamoyl-Phosphate Synthase I Deficiency Disease, Ammonia, Citrulline, Phenotype, Glutamic Acid, Mutation, Carbamoyl phosphate synthetase 1 deficiency, Human mutation, Enzyme activity, Hyperammonemia, Glutamine
Published Open-Access
yes
Recommended Citation
Bakshi, Stuti; Diep, Taryn; Willis, Brandon J; et al., "A Hypomorphic Model of CPS1 Deficiency for Investigating the Effects of Hyperammonemia on the Developing Nervous System" (2025). Faculty and Staff Publications. 5182.
https://digitalcommons.library.tmc.edu/baylor_docs/5182
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