title: Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations.
abstract: Citrullinemia type 1 is an autosomal recessive urea cycle disorder caused by defects in the argininosuccinate synthetase (ASS) enzyme due to mutations in ASS1 gene. An impairment of ASS function can lead to a wide spectrum of phenotypes, from life-threatening neonatal hyperammonemia to a later onset with mild symptoms, and even some asymptomatic patients exhibiting an only biochemical phenotype. The disease is panethnic. In this update, we report 137 mutations (64 of which are novel), consisting of 89 missense mutations, 19 nonsense mutations, 17 mutations that affect splicing, and 12 deletions. The change p.Gly390Arg is by far the most common mutation and is widely spread throughout the world. Other frequent mutations (p.Arg157His, p.Trp179Arg, p.Val263Met, p.Arg304Trp, p.Gly324Ser, p.Gly362Val, and p.Arg363Trp), each found in at least 12 independent families, are mainly carried by patients from the Indian subcontinent, Turkey, Germany, and Japan. To better understand the disease, we collected clinical data of >360 patients, including all published information available. This information is related to the patients' genetic background, the conservation of the mutated residues and a structural rationalization of the effect of the most frequent mutations. In addition, we review ASS regulation, animal models, diagnostic strategies, newborn screening, and treatment options.
authors.affiliation: Division of Metabolism, University Children´s Hospital and Children's Research Center, Zurich, Switzerland.
authors.forename: Carmen
authors.initials: C
authors.lastname: Diez-Fernandez
authors.affiliation: Division of Metabolism, University Children´s Hospital and Children's Research Center, Zurich, Switzerland.
authors.forename: Véronique
authors.initials: V
authors.lastname: Rüfenacht
authors.affiliation: Division of Metabolism, University Children´s Hospital and Children's Research Center, Zurich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Häberle
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001124:Argininosuccinate Synthase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020159:Citrullinemia / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy; D004195:Disease Models, Animal; D004789:Enzyme Activation; D056726:Genetic Association Studies; D005838:Genotype; D062306:Geography, Medical; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D056510:Position-Specific Scoring Matrices; D011296:Prenatal Diagnosis; D011487:Protein Conformation; D012720:Severity of Illness Index; D013329:Structure-Activity Relationship
chemical_list: D001124:Argininosuccinate Synthase
keywords: ASS1; argininosuccinate synthetase; citrullinemia type 1; hyperammonemia; inherited metabolic disorder; urea cycle disorder