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Analysis of novel ARG1 mutations causing hyperargininemia and correlation with arginase I activity in erythrocytes
Authors:Daniel Rocha Carvalho  Guilherme Dotto Brand  Jaime Moritz Brum  Reinaldo Issao Takata  Carlos Eduardo Speck-Martins  Riccardo Pratesi
Institution:Genetic Unit, SARAH Rehabilitation Hospital, SMHS Quadra 501 Conj. A, Brasilia, Distrito Federal, 70335-901, Brazil; School of Medicine, Brasilia University, Sala BC-212, Campus Universitario, Brasilia, Distrito Federal, 70910-900, Brazil. Electronic address: danielcarvalho@sarah.br.
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.
Keywords:ARG1  enzyme arginase I  ARG1  gene of arginase I  ARG2  enzyme arginase II  ARG2  gene of arginase II  EC  Enzyme Commission number  HA  hyperargininemia  MT  mutated protein  OMIM ID  identifier in the Online Mendelian Inheritance in Man  WT  wild-type protein
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