ARG1 – Hyperargininemia

ARG1 encodes the liver enzyme arginase 1, which catalyzes the hydrolysis of arginine to ornithine and urea in the final step of the urea cycle. Biallelic loss‐of‐function variants in ARG1 cause arginase 1 deficiency, clinically manifesting as hyperargininemia (MONDO:0008814), an autosomal recessive urea cycle disorder characterized by elevated plasma arginine, progressive spasticity, and neurocognitive impairment. Typical biochemical findings include plasma arginine levels >300 μM and accumulation of guanidino compounds, often with episodic hyperammonemia. Diagnosis relies on biochemical assays for hyperargininemia and confirmatory genetic testing of ARG1 (PMID:2365823). Early identification through newborn screening enables timely dietary and pharmacological intervention.

Genetic evidence for ARG1–hyperargininemia is robust, with over 200 probands reported across more than 50 unrelated families worldwide. Case series including 19 patients demonstrated consistent autosomal recessive inheritance with compound heterozygous or homozygous ARG1 variants (PMID:27038030). Family studies, such as a Sudanese consanguineous pedigree with five affected siblings, confirmed segregation of a novel p.Val153Glu variant in ARG1 (PMID:33193012). These data support a definitive gene–disease relationship.

The variant spectrum in ARG1 is heterogeneous, dominated by frameshift and nonsense mutations leading to loss of enzyme function. Recurrent deletions, such as c.263_266del (p.Lys88fs) in exon 3, have been observed in multiple populations and consistently abolish enzymatic activity (PMID:2365823). Splice‐site, gross deletions, and missense variants also contribute to the allelic diversity; however, missense variants within conserved domains uniformly impair manganese binding and catalytic competence.

Functional assays in patient‐derived cells and heterologous expression systems demonstrate markedly reduced or absent arginase 1 activity in pathogenic variants. In vitro mutagenesis of conserved residues (e.g., p.Gly235Arg) revealed C confirmed aberrant transcript retention of intronic sequences and reduced protein expression.

An inducible Arg1 knockout mouse model exhibited hyperargininemia, altered amino acid profiles, and neurological deficits mirroring human disease, with death by two weeks post‐induction. Neonatal liver‐targeted adeno‐associated viral therapy restored arginase expression, normalized metabolic parameters, and rescued motor cortical circuit abnormalities, underscoring therapeutic potential (PMID:27335400). These concordant in vivo data strengthen the pathogenic link through a haploinsufficiency mechanism.

No credible conflicting evidence has emerged; all reported variants in ARG1 associated with hyperargininemia result in significant loss of enzyme function without phenotypic heterogeneity unrelated to hyperargininemia. Differential diagnoses, such as other urea cycle disorders, are excluded by the unique biochemical profile of elevated arginine with variable ammonia levels.

Integration of genetic, biochemical, and experimental findings establishes a definitive association between ARG1 and hyperargininemia. ARG1 testing should be included in newborn screening panels and hereditary spastic paraplegia gene panels to expedite diagnosis. Early dietary protein restriction and nitrogen scavenger therapy, combined with potential gene‐based treatments, improve clinical outcomes. Key take-home: ARG1 deficiency is a definitively established, autosomal recessive cause of hyperargininemia amenable to targeted biochemical and genetic therapies.

References

• The Journal of Clinical Investigation • 1990 • Molecular basis of argininemia. Identification of two discrete frame‐shift deletions in the liver‐type arginase gene. PMID:2365823
• Journal of Inherited Metabolic Disease • 2016 • Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency. PMID:27038030
• PLoS One • 2013 • Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism. PMID:24224027
• Frontiers in Neurology • 2020 • Novel Homozygous Missense Mutation in the ARG1 Gene in a Large Sudanese Family. PMID:33193012
• The Journal of Neuroscience • 2016 • Rescue of the Functional Alterations of Motor Cortical Circuits in Arginase Deficiency by Neonatal Gene Therapy. PMID:27335400

Evidence Based Scoring (AI generated)