Molecular Genetics of Argininosuccinic Aciduria


Argininosuccinic aciduria is an autosomal recessive disorder of the urea cycle caused by mutations in argininosuccinate lyase (ASL). Two main clinical phenotypes are reported: an acute neonatal form characterised by severe hyperammonaemia and coma, and a subacute, late‐onset form which may present with relatively milder neurological symptoms.

More than 120 ASL mutations have been reported so far: the majority are missense, but virtually all types of point mutations are found. Large rearrangements are rare and standard genomic deoxyribonucleic acid (DNA) analysis has a high diagnostic yield.

Genotype–phenotype correlations have been difficult to establish as standard biochemical techniques are not sufficiently sensitive to measure residual activity, and other factors such as intragenic complementation, overexpression of nonfunctional ASL transcripts and environmental factors may modulate the phenotype.

Clinical manifestations result from the block in the urea cycle and also from impairment of nitric oxide biosynthesis, and the therapy is aimed at restoring these two functions.

Key Concepts:

  • Argininosuccinic aciduria is caused by deficiency of argininosuccinate lyase (ASL).

  • ASL is a component of the urea cycle and is essential for detoxification of ammonia, and for the synthesis of arginine and nitric oxide (NO).

  • Two clinical forms of argininosuccinic aciduria exist: an acute, potentially lethal, neonatal onset disease and a milder, late‐onset form.

  • More than 120 ASL mutations have been described but the exact genotype/phenotype correlations are still not completely clear.

  • Other factors (genetic and environmental) may influence the clinical phenotype.

  • Treatment is based on protein restriction, arginine, nitrogen scavengers and NO donors.

Keywords: urea cycle; argininosuccinate lyase; nitric oxide; hyperammonaemia; intragenic complementation; molecular diagnosis; animal models

Figure 1.

(a) Structure of the ASL tetramer. Arrowheads indicate the active sites. In yellow is argininosuccinic acid. (b) Structure of the ASL monomer with the three domains depicted in different colours.

Figure 2.

(a) Heterotetramer formed by the p.R113Q and p.Q286R mutants. Arrowheads indicate mutant residues (which are represented in red). The yellow circles indicate ‘normal’ active sites; the red circles indicate active sites containing mutant residues. (b) Heterotetramer formed by the p.R113Q and p.R236W mutants. No ‘normal’ active sites can be formed. (c) Position of residues arginine 113, arginine 236 and glutamine 286 within the different ASL domains. In pink is the substrate (ASA).



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Further Reading

Brusilow S and Horwich A (2001) Urea cycle enzymes. In: Scriver C , Beaudet A , Sly W , Valle D (eds) The Metabolic & Molecular Bases of Inherited Disease, pp. 1909–1963. New York: McGraw‐Hill.

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Trevisson, Eva, Doimo, Mara, and Salviati, Leonardo(May 2014) Molecular Genetics of Argininosuccinic Aciduria. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025353]