ASL – Argininosuccinic Aciduria

Argininosuccinic aciduria is an autosomal recessive urea cycle disorder caused by biallelic pathogenic variants in the ASL gene (ASL). Patients present with hyperammonemia, hepatomegaly, neurodevelopmental delay, seizures, and variable liver fibrosis. The association between ASL and argininosuccinic aciduria has been established over three decades by genetic, enzymatic, and animal model studies, fulfilling criteria for a definitive gene–disease relationship.

Genetic evidence includes identification of pathogenic variants in at least 27 unrelated probands with classical and late-onset presentations ([PMID:12384776]). The variant spectrum comprises missense, nonsense, splice-site, frameshift, and deep intronic changes. A recurrent stop mutation, c.1060C>T (p.Gln354Ter), accounts for 50% of alleles in Saudi patients ([PMID:16435180]). Other common variants include p.Arg95Cys and p.Leu440Pro in newborn-screened cohorts ([PMID:37865865]). The overall allelic heterogeneity, with over 160 genotypes reported in 223 patients, supports autosomal recessive inheritance and robust clinical validity.

Segregation analysis has demonstrated co-segregation of ASL variants with disease in consanguineous and non-consanguineous families. The homozygous R95C mutation was shown in a late-onset patient with A) confirming aberrant transcript inclusion ([PMID:31156699]).

Functional studies establish loss of ASL activity and protein instability as the predominant mechanisms of pathogenesis. Recombinant expression in human cells and bacterial systems demonstrated that variants such as p.Arg95Cys, p.Ile100Thr, and p.Val178Met confer residual activity but display thermal instability and disrupted tetramer formation ([PMID:25778938]). In vivo, ASL-deficient mice exhibit blood–brain barrier leakage mediated by nitric oxide deficiency, which is partially rescued by NO donors, linking enzyme loss to neurovascular dysfunction ([PMID:37490345]).

Therapeutic development includes screening of chaperones like cysteamine for cysteine-for-arginine substitutions and advanced mRNA–LNP approaches. In a hypomorphic ASL^Neo/Neo mouse model, intravenous administration of nucleoside-modified ASL mRNA formulated in lipid nanoparticles restored enzyme expression and fully prevented mortality at 3 mg/kg dosing ([PMID:37371829]).

In summary, ASL deficiency is a well-characterized autosomal recessive disorder with definitive clinical validity. Comprehensive genetic testing of ASL, supported by functional assays, informs diagnosis, allows newborn screening follow-up, and guides emerging mRNA-based therapies. ASL variant analysis is essential for precise diagnosis, prognostication, carrier screening, and therapeutic stratification.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1990 • Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region. PMID:2263616
• Human genetics • 2002 • Argininosuccinate lyase deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene. PMID:12384776
• Frontiers in genetics • 2019 • Functional Characterization of Argininosuccinate Lyase Gene Variants by Mini-Gene Splicing Assay. PMID:31156699
• JCI insight • 2023 • Argininosuccinate lyase deficiency causes blood-brain barrier disruption via nitric oxide-mediated dysregulation of claudin expression. PMID:37490345
• Biomedicines • 2023 • ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model. PMID:37371829

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