Dis Model Mech. 2025 May 27:dmm.052303. doi: 10.1242/dmm.052303. Online ahead of print.
ABSTRACT
Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a rare metabolic disorder that in neonatal onset is typically characterized with 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 hours of birth, limiting study capabilities. Herein, we developed a novel Cps1 hypomorphic murine model with residual enzyme activity that maintains survival, but with reduction that dysfunction of Cps1 could be detected biochemically. Characterization, based on the orthologous human mutation Asn674Ile, revealed that it 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.
PMID:40421838 | DOI:10.1242/dmm.052303
