Contrasting features of urea cycle disorders in human patients and knockout mouse models

Abstract

The urea cycle exists for the removal of excess nitrogen from the body. Six separate enzymes comprise the urea cycle, and a deficiency in any one of them causes a urea cycle disorder (UCD) in humans. Arginase is the only urea cycle enzyme with an alternate isoform, though no known human disorder currently exists due to a deficiency in the second isoform. While all of the UCDs usually present with hyperammonemia in the first few days to months of life, most disorders are distinguished by a characteristic profile of plasma amino acid alterations that can be utilized for diagnosis. While enzyme assay is possible, an analysis of the underlying mutation is preferable for an accurate diagnosis. Mouse models for each of the urea cycle disorders exist (with the exception of NAGS deficiency), and for almost all of them, their clinical and biochemical phenotypes rather closely resemble the phenotypes seen in human patients. Consequently, all of the current mouse models are highly useful for future research into novel pharmacological and dietary treatments and gene therapy protocols for the management of urea cycle disorders.

Arginase: an old enzyme with new tricks

“…However, most non-hepatic tissues lack CPS-1 or OTC and therefore do not have the complete urea cycle. Dysregulation of urea cycle enzymes can result in hyperammonemia, and if left untreated, will cause seizures, mental disorders and early morbidity [105]. Treatment of patients with A1 deficiency involves decreasing protein intake, dietary supplementation with essential amino acids, and in severe cases orthotropic liver transplant [105].…”

Proteome analysis in the assessment of ageing

“…Furthermore, the more than six-fold decrease in ornithine transcarbamylase (OTC) will affect the urea cycle and l-arginine biosynthesis in the aged rats. In humans, severe OTC deficiency may result in hyperammonemia and in turn, without intervention, in metabolic encephalopathy, coma, and eventually death (Deignan et al, 2008;Walker, 2009).…”

Cell and Gene Therapy for Carbamoyl Phosphate Synthetase 1 Deficiency

“…Therefore, all the current mouse models are highly useful for gene therapy studies [15]. To study gene therapies directed to the hepatocytes to treat CPS1 deficiency, Schofield et al generated a CPS1 deficient mouse by gene targeting.…”