Hyperargininemia due to liver arginase deficiency
Department of Pediatrics, University of California, Los Angeles, Los Ángeles, California, United States Molecular Genetics and Metabolism
(Impact Factor: 2.63).
04/2005; 84(3):243-51. DOI: 10.1016/j.ymgme.2004.11.004
The urea cycle is a series of six reactions necessary to rid the body of the nitrogen generated by the metabolism, primarily of amino acids, from the diet or released as the result of endogenous protein catabolism. Arginase is the sixth and final enzyme of this cycle. Arginase catalyzes the conversion of arginine to urea and ornithine, the latter recycled to continue the cycle. Hyperargininemia due to arginase deficiency is inherited in an autosomal recessive manner and gene for arginase, designated AI, has been cloned. Unlike the other urea cycle enzymes, a second gene encoding arginase, with similar structural properties and enzyme characteristics, exists and has been named Arginase II (AII). Comprehensive histories and physical examinations confirm a strikingly uniform clinical picture and one notably different from patients with other urea cycle disorders. This condition rarely presents in the neonatal period and first symptoms typically present in children between 2 and 4 years of age. First symptoms are often neurologically based. If untreated, symptoms are progressive with a gradual loss of developmental milestones. With adherence to a dietary and drug regimen, a favorable outcome can be expected, with cessation of further neurological deterioration and in some instances, of improvement. This article summarizes the clinical course of selected patients who represent the full spectrum of presentations of arginase deficiency. In addition to the clinical characterization of this disorder; the biochemical, enzymatic, and molecular evidence of disease is summarized. Treatment and prenatal diagnosis are also discussed.
Available from: Laurel Ballantyne
- "This deficiency is transmitted in an autosomal recessive manner and often leads to hyperargininemia, a metabolic disorder characterized by progressive neurological and intellectual impairment, spasticity and persistent growth retardation . Some patients may also display intermittent episodes of behavior disturbance (irritability, hyperactivity and aggression), feeding difficulties, vomiting, lethargy and seizures . Unlike other urea cycle disorders with early-onset presentation, hyperargininemia usually presents after the neonatal period, particularly between two to four years of age with predominantly neurological manifestations and infrequent episodes of hyperammonemia. "
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ABSTRACT: Arginase deficiency is a rare autosomal recessive disorder resulting from a loss of the liver arginase isoform, arginase 1 (ARG1), which is the final step in the urea cycle for detoxifying ammonia. ARG1 deficiency leads to hyperargininemia, characterized by progressive neurological impairment, persistent growth retardation and infrequent episodes of hyperammonemia. Using the Cre/loxP-directed conditional gene knockout system, we generated an inducible Arg1-deficient mouse model by crossing "floxed" Arg1 mice with CreER(T2) mice. The resulting mice (Arg-Cre) die about two weeks after tamoxifen administration regardless of the starting age of inducing the knockout. These treated mice were nearly devoid of Arg1 mRNA, protein and liver arginase activity, and exhibited symptoms of hyperammonemia. Plasma amino acid analysis revealed pronounced hyperargininemia and significant alterations in amino acid and guanidino compound metabolism, including increased citrulline and guanidinoacetic acid. Despite no alteration in ornithine levels, concentrations of other amino acids such as proline and the branched-chain amino acids were reduced. In summary, we have generated and characterized an inducible Arg1-deficient mouse model exhibiting several pathologic manifestations of hyperargininemia. This model should prove useful for exploring potential treatment options of ARG1 deficiency.
PLoS ONE 11/2013; 8(11):e80001. DOI:10.1371/journal.pone.0080001 · 3.23 Impact Factor
Available from: Zhihong Yang
- "Arg-I deficiency due to gene mutation has been identified and characterized in humans. These patients reveal urea cycle disorder, hyperargininemia and exhibit neurologically based clinical symptoms in early childhood, including progressive neurologic impairment, development retardation, and hepatic dysfunction associated with cirrhosis and carcinoma (Crombez and Cederbaum, 2005; Tsang et al., 2012). Although this enzyme is largely confined to the liver, it is also present in many extrahepatic tissues such as stomach, pancreas, and lung (Choi et al., 2012). "
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ABSTRACT: Oxidative stress and inflammation in the vascular wall are essential mechanisms of atherosclerosis and vascular dysfunctions associated with risk factors such as metabolic diseases, aging, hypertension, etc. Evidence has been provided that activation of the vascular endothelial cells in the presence of the risk factors promotes oxidative stress and vascular inflammatory responses, leading to acceleration of atherosclerotic vascular disease. Increasing number of studies from recent years demonstrates that uncoupling of endothelial nitric oxide synthase (eNOS), whereby the enzyme eNOS produces detrimental amount of superoxide anion [Formula: see text] instead the vasoprotective nitric oxide (NO(⋅)), plays a critical role in vascular dysfunction under various pathophysiological conditions and in aging. The mechanisms of eNOS-uncoupling seem multiple and complex. Recent research provides emerging evidence supporting an essential role of increased activity of arginases including arginase-I and arginase-II in causing eNOS-uncoupling, which results in vascular oxidative stress and inflammatory responses, and ultimately leading to vascular diseases. This review article will summarize the most recent findings on the functional roles of arginases in vascular diseases and/or dysfunctions and the underlying mechanisms in relation to oxidative stress and inflammations. Moreover, regulatory mechanisms of arginases in the vasculature are reviewed and the future perspectives of targeting arginases as therapeutic options in vascular diseases are discussed.
Frontiers in Immunology 06/2013; 4:149. DOI:10.3389/fimmu.2013.00149
Available from: Guilherme Dotto Brand
- "Missense mutations occurring in highly conserved regions of the gene are the most frequent. The variation in the clinical severity of HA cannot be explained by the differences in the nature of ARG1 mutations, and a clear genotype–phenotype correlation has not yet been described for this disease (Crombez and Cederbaum, 2005; Scaglia and Lee, 2006; Vockley et al., 1996). "
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ABSTRACT: Hyperargininemia (HA) is an autosomal recessive disease that typically has a clinical presentation that is distinct from other urea cycle disorders. It is caused by the deficient activity of the enzyme arginase I, encoded by the gene ARG1. We screened for ARG1 mutations and measured erythrocyte enzyme activity in a series of 16 Brazilian HA patients. Novel mutations, in addition to previously described missense mutations, were analysed for their effect on the structure, stability and/or function of arginase I (ARG1) using bioinformatics tools. Three previously reported mutations were found (p.R21X; p.I11T and p.W122X), and five novel mutations were identified (p.G27D; p.G74V; p.T134I; p.R308Q; p.I174fs179). The p.T134I mutation was the most frequent in the Brazilian population. Patients carrying the p.R308Q mutation had higher residual ARG1 decreased activity, but presented no distinguishable phenotype compared to the other patients. Bioinformatics analyses revealed that missense mutations (1) affect the ARG1 active site, (2) interfere with the stability of the ARG1 folded conformation or (3) alter the quaternary structure of the ARG1. Our study reinforced the role of Arg308 residue for assembly of the ARG1 homotrimer. The panel of heterogeneous ARG1 mutations that cause HA was expanded, nevertheless a clear genotype-phenotype correlation was not observed in our series.
Gene 08/2012; 509(1):124-30. DOI:10.1016/j.gene.2012.08.003 · 2.14 Impact Factor
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