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MURINE MODEL FOR N‐ACETYLGLUTAMATE SYNTHASE (NAGS) DEFICIENCY
Author(s) -
Mirzozoda Khulkar,
CabreraLuque Juan,
Caldovic Ljubica,
Morizono Hiroki,
Tuchman Mendel
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.917.3
Subject(s) - hyperammonemia , urea cycle , medicine , endocrinology , weaning , atp synthase , urea , enzyme , biology , biochemistry , arginine , amino acid
Ammonia is channeled into the urea cycle by means of carbamylphosphate synthetase (CPS1). This initial step of urea synthesis takes place in the mitochondria of the liver cell and requires N‐acetylglutamate (NAG). NAG is an essential cofactor and activator of CPS1 which is formed from AcCoA and glutamate by the enzyme N‐acetylglutamate synthase (NAGS). The lack of NAGS enzyme or its activity leads to severe neonatal hyperammonemia due to the inability of CPS1 to synthesize CP in the absence of NAG. NAGS deficiency is one of the more rare urea cycle disorders. In patients with NAGS deficiency, treatment with N‐carbamylglutamate (NCG) fully restores ureagenesis by activating CPS1. We have recently created a novel mouse model of NAGS deficiency using the VelociGene gene ablation method via the NIH‐funded KOMP resource. Following heterozygous mating, we have attempted to rescue homozygous NAGS deficient mice by providing NCG to the pregnant females in drinking water during pregnancy extending the life of homozygous pups for a period of 60 to 120 hours after birth, while untreated mice died within 24 hours after birth. We have subsequently been able to extend the lifespan of a homozygous NAGSko female for 12 days while a homozygous NAGSko male has survived pass weaning age using a combination of NCG and citrulline. This model recapitulates clinical observations in human and seems to be suitable model of the human disorder.