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A novel biochemically salvageable animal model of hyperammonemia devoid of N-acetylglutamate synthase

Content Provider	PubMed Central
Author	Senkevitch, Emilee Juan, Cabrera-luque Morizono, Hiroki Caldovic, Ljubica Tuchman, Mendel
Copyright Year	2012
Abstract	All knockout mouse models of urea cycle disorders die in the neonatal period or shortly thereafter. Since N-acetylglutamate synthase (NAGS) deficiency in humans can be effectively treated with N-carbamyl-L-glutamate (NCG), we sought to develop a mouse model of this disorder that could be rescued by biochemical intervention, reared to adulthood, reproduce, and become a novel animal model for hyperammonemia. Founder NAGS knockout heterozygous mice were obtained from the trans-NIH Knock-Out Mouse Project. Genotyping of the mice was performed by PCR and confirmed by Western blotting of liver and intestine. NCG and L-citrulline (Cit) were used to rescue the NAGS knockout homozygous (Nags −/−) pups and the rescued animals were characterized. We observed an 85% survival rate of Nags −/− mice when they were given intraperitoneal injections with NCG and Cit during the newborn period until weaning and supplemented subsequently with both compounds in their drinking water. This regimen has allowed for normal development, apparent health, and reproduction. Interruption of this rescue intervention resulted in the development of severe hyperammonemia and death within 48 hours. In addition to hyperammonemia, interruption of rescue supplementation was associated with elevated plasma glutamine, glutamate, and lysine, and reduced citrulline, arginine, ornithine and proline levels. We conclude that NAGS deprived mouse model has been developed which can be rescued by NCG and Cit and reared to reproduction and beyond. This biochemically salvageable mouse model recapitulates the clinical phenotype of proximal urea cycle disorders and can be used as a reliable model of induced hyperammonemia by manipulating the administration of the rescue compounds.
Related Links	http://dx.doi.org/10.1016/j.ymgme.2012.03.004
Ending Page	168
Page Count	9
Starting Page	160
File Format	PDF
ISSN	10967192
e-ISSN	10967206
Journal	Molecular Genetics and Metabolism
Issue Number	2
Volume Number	106
Language	English
Publisher Date	2012-06-01
Access Restriction	Open
Subject Keyword	Genetics Biochemistry Molecular Biology Endocrinology, Diabetes and Metabolism Endocrinology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics Endocrinology, Diabetes and Metabolism Biochemistry Molecular Biology Endocrinology

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