Contract grant sponsor: The Swiss National Science Foundation (310030_127184/1, 310031_134926); Schweizerische Mobiliar Genossenschaft Jubiläumsstiftung.
Mutations and Polymorphisms in the Human Argininosuccinate Lyase (ASL) Gene
Article first published online: 25 NOV 2013
© 2013 WILEY PERIODICALS, INC.
Volume 35, Issue 1, pages 27–35, January 2014
How to Cite
Balmer, C., Pandey, A. V., Rüfenacht, V., Nuoffer, J.-M., Fang, P., Wong, L.-J. and Häberle, J. (2014), Mutations and Polymorphisms in the Human Argininosuccinate Lyase (ASL) Gene. Hum. Mutat., 35: 27–35. doi: 10.1002/humu.22469
Communicated by Hans R. Waterham
- Issue published online: 18 DEC 2013
- Article first published online: 25 NOV 2013
- Accepted manuscript online: 25 OCT 2013 11:43AM EST
- Manuscript Accepted: 9 OCT 2013
- Manuscript Received: 12 JUL 2013
- The Swiss National Science Foundation. Grant Numbers: 310030_127184/1, 310031_134926
- Schweizerische Mobiliar Genossenschaft Jubiläumsstiftung
- argininosuccinate lyase;
- argininosuccinic aciduria;
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.