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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\u2005h 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.<\/jats:p>","DOI":"10.1242\/dmm.052303","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T11:46:03Z","timestamp":1748346363000},"source":"Crossref","is-referenced-by-count":3,"title":["A hypomorphic model of CPS1 deficiency for investigating the effects of hyperammonemia on the developing nervous system"],"prefix":"10.1242","volume":"18","author":[{"given":"Stuti","family":"Bakshi","sequence":"first","affiliation":[{"name":"David Geffen School of Medicine at UCLA 1 Departments of Surgery , , Los Angeles, CA 90095 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taryn","family":"Diep","sequence":"additional","affiliation":[{"name":"David Geffen School of Medicine at UCLA 1 Departments of Surgery , , Los Angeles, CA 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