ASS1 – Citrullinemia Type I

ASS1 (argininosuccinate synthetase 1) deficiency underlies autosomal recessive citrullinemia type I, a urea cycle disorder characterized by elevated plasma citrulline and hyperammonemia leading to neurological and hepatic manifestations. The gene–disease relationship is supported by extensive case reports and large-scale mutation analyses demonstrating biallelic loss-of-function variants in ASS1 ASS1 – Citrullinemia.

Numerous case studies describe compound heterozygous and homozygous ASS1 variants. A woman with asymptomatic CTLN1 carried IVS15-1G>C and c.928A>C (p.Lys310Gln) and completed two pregnancies without crisis (PMID:15266621). Late-onset presentations include episodic ataxia in an 11-year-old with homozygous c.815G>A (p.Arg272His) (PMID:29695388).

Large cohort studies identify over 360 patients with biallelic ASS1 mutations, spanning 137 distinct variants including missense, nonsense, splice-site, and small indels. Common alleles such as c.1168G>A (p.Gly390Arg) recur globally, while population-specific hotspots (e.g., IVS6-2A>G in East Asians) illustrate allelic heterogeneity and founder effects (PMID:28111830).

Functional assays in bacterial expression systems confirm that mutant ASS1 proteins have reduced stability or activity; for instance, p.Ala118Thr retains only 13% of wild-type activity, and p.Arg272Cys shows markedly increased Km (PMID:8792870). Kinetic rescue experiments demonstrate that eight missense mutants with decreased substrate affinity can be partially restored by high aspartate levels, supporting therapeutic substrate supplementation (PMID:27287393).

In vivo models further corroborate pathogenicity: zebrafish ass1 knockdown causes defective neuronal differentiation and brain hypoplasia that are rescued by human ASS1 mRNA injection, indicating a conserved loss-of-function mechanism (PMID:38113552). Likewise, mouse hypomorphic Ass1 alleles recapitulate hyperammonemia, cerebellar delays, and cutaneous features observed in CTLN1 patients, amenable to standard treatments (PMID:20724589).

Key Take-home: ASS1 genetic testing is essential for early diagnosis, prognostic counseling, and guiding interventions—ranging from dietary management to emerging substrate supplementation strategies—in citrullinemia type I.

References

• Human Mutation • 2017 • Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations PMID:28111830
• Molecular Genetics and Metabolism • 2016 • Kinetic mutations in argininosuccinate synthetase deficiency: characterisation and in vitro correction by substrate supplementation PMID:27287393
• Enzyme & Protein • 1994 • Characterization of human wild-type and mutant argininosuccinate synthetase proteins expressed in bacterial cells PMID:8792870
• American Journal of Pathology • 2010 • Two hypomorphic alleles of mouse Ass1 as a new animal model of citrullinemia type I and other hyperammonemic syndromes PMID:20724589
• Stem Cell Research • 2018 • Generation of an ASS1 heterozygous knockout human embryonic stem cell line, WAe001-A-13, using CRISPR/Cas9 PMID:29247816
• American Journal of Medical Genetics Part A • 2004 • Pregnancy in a healthy woman with untreated citrullinemia PMID:15266621
• BMJ Case Reports • 2018 • Hypomorphic citrullinaemia due to mutated ASS1 with episodic ataxia PMID:29695388
• Molecular Genetics and Metabolism • 2024 • ASS1 deficiency is associated with impaired neuronal differentiation in zebrafish larvae PMID:38113552

Evidence Based Scoring (AI generated)