title: A new mouse model of mild ornithine transcarbamylase deficiency (spf-j) displays cerebral amino acid perturbations at baseline and upon systemic immune activation.
abstract: Ornithine transcarbamylase deficiency (OTCD, OMIM# 311250) is an inherited X-linked urea cycle disorder that is characterized by hyperammonemia and orotic aciduria. In this report, we describe a new animal model of OTCD caused by a spontaneous mutation in the mouse Otc gene (c.240T>A, p.K80N). This transversion in exon 3 of ornithine transcarbamylase leads to normal levels of mRNA with low levels of mature protein and is homologous to a mutation that has also been described in a single patient affected with late-onset OTCD. With higher residual enzyme activity, spf-J were found to have normal plasma ammonia and orotate. Baseline plasma amino acid profiles were consistent with mild OTCD: elevated glutamine, and lower citrulline and arginine. In contrast to WT, spf-J displayed baseline elevations in cerebral amino acids with depletion following immune challenge with polyinosinic:polycytidylic acid. Our results indicate that the mild spf-J mutation constitutes a new mouse model that is suitable for mechanistic studies of mild OTCD and the exploration of cerebral pathophysiology during acute decompensation that characterizes proximal urea cycle dysfunction in humans.
authors: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Tatyana N
authors: TN
authors: Tarasenko
authors: Universidad Central de Caribe, Bayamon, Puerto Rico, United States of America.
authors: Odrick R
authors: OR
authors: Rosas
authors: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Larry N
authors: LN
authors: Singh
authors: Department of Neurogenetics, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors: Kara
authors: K
authors: Kristaponis
authors: Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors: Hilary
authors: H
authors: Vernon
authors: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Peter J
authors: PJ
authors: McGuire
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001835:Body Weight; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009954:Ornithine Carbamoyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020163:Ornithine Carbamoyltransferase Deficiency Disease / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D009963:Orotic Acid / Q000378:metabolism; D010641:Phenotype; D011070:Poly I-C / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051381:Rats; D016019:Survival Analysis
chemical_list: D000596:Amino Acids; D009963:Orotic Acid; D009954:Ornithine Carbamoyltransferase; D011070:Poly I-C
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