title: Mutations and polymorphisms in the human argininosuccinate lyase (ASL) gene.
abstract: Argininosuccinate lyase deficiency (ASLD) is caused by a defect of the urea cycle enzyme argininosuccinate lyase (ASL) encoded by the ASL gene. Patients often present early after birth with hyperammonemia but can also manifest outside the neonatal period mainly triggered by excessive protein catabolism. Clinical courses comprise asymptomatic individuals who only excrete the biochemical marker, argininosuccinic acid, in urine, and patients who succumb to their first hyperammonemic decompensation. Some patients without any hyperammonemia develop severe neurological disease. Here, we are providing an update on the molecular basis of ASLD by collecting all published (n = 67) as well as novel mutations (n = 67) of the ASL gene. We compile data on all 160 different genotypes ever identified in 223 ASLD patients, including clinical courses whenever available. Finally, we are presenting structural considerations focusing on the relevance of mutations for ASL homotetramer formation. ASLD can be considered as a panethnic disease with only single founder mutations identified in the Finnish (c.299T>C, p.Ile100Thr) and Arab (c.1060C>T, p.Gln354*) population. Most mutations are private with only few genotypes recurring in unrelated patients. The majority of mutations are missense changes including some with more frequent occurrence such as p.Arg12Gln, p.Ile100Thr, p.Val178Met, p.Arg186Trp, p.Glu189Gly, p.Gln286Arg, and p.Arg385Cys.
authors.affiliation: Division of Metabolism, University Children's Hospital, Zurich, Switzerland; Children's Research Center, Zurich, Switzerland.
authors.forename: Cécile
authors.initials: C
authors.lastname: Balmer
authors.forename: Amit V
authors.initials: AV
authors.lastname: Pandey
authors.forename: Véronique
authors.initials: V
authors.lastname: Rüfenacht
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Nuoffer
authors.forename: Ping
authors.initials: P
authors.lastname: Fang
authors.forename: Lee-Jun
authors.initials: LJ
authors.lastname: Wong
authors.forename: Johannes
authors.initials: J
authors.lastname: Häberle
mesh_terms: D001123:Argininosuccinate Lyase / Q000737:chemistry* / Q000235:genetics*; D056807:Argininosuccinic Aciduria / Q000208:ethnology / Q000235:genetics*; D001665:Binding Sites; D018389:Codon, Nonsense; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary
chemical_list: D018389:Codon, Nonsense; D001123:Argininosuccinate Lyase
keywords: ASA; ASL; argininosuccinate lyase; argininosuccinic aciduria; hyperammonemia