title: Analysis of novel ARG1 mutations causing hyperargininemia and correlation with arginase I activity in erythrocytes.
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.
authors.affiliation: Genetic Unit, SARAH Rehabilitation Hospital, SMHS Quadra 501 Conj. A, Brasilia, Distrito Federal, 70335-901, Brazil. danielcarvalho@sarah.br
authors.forename: Daniel Rocha
authors.initials: DR
authors.lastname: Carvalho
authors.forename: Guilherme Dotto
authors.initials: GD
authors.lastname: Brand
authors.forename: Jaime Moritz
authors.initials: JM
authors.lastname: Brum
authors.forename: Reinaldo Issao
authors.initials: RI
authors.lastname: Takata
authors.forename: Carlos Eduardo
authors.initials: CE
authors.lastname: Speck-Martins
authors.forename: Riccardo
authors.initials: R
authors.lastname: Pratesi
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001119:Arginase / Q000097:blood* / Q000737:chemistry / Q000235:genetics*; D001120:Arginine / Q000097:blood; D001938:Brazil; D020134:Catalytic Domain / Q000235:genetics; D002648:Child; D004252:DNA Mutational Analysis; D004789:Enzyme Activation / Q000235:genetics; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D020162:Hyperargininemia / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000097:blood* / Q000737:chemistry / Q000235:genetics*; D020125:Mutation, Missense; D011487:Protein Conformation; D017510:Protein Folding; D055503:Protein Multimerization / Q000235:genetics; D020836:Protein Structure, Quaternary / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D055815:Young Adult
chemical_list: D050505:Mutant Proteins; D001120:Arginine; C574619:ARG1 protein, human; D001119:Arginase