ASS1 variants cause citrullinemia

Stable Identifier
R-HSA-9956520
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Pathway
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Homo sapiens
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3/5
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ASS1 variants cause citrullinemia
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Argininosuccinate synthase (ASS1) plays a critical role in the detoxification of ammonia, catalyzing the third step of the urea cycle, the ATP-dependent condensation of citrulline and aspartate to yield argininosuccinate (Diez-Fernandez et al, 2016; Shaheen et al, 1994; Berning et al, 2008). ASS1 is a cytosolic enzyme that is expressed at highest levels in hepatocytes, but is also expressed in the kidney at lower levels.
Mutations in ASS1 cause type 1 citrullinemia (OMIM 215700), an autosomal recessive inborn error of metabolism affecting ~ 1 in 250,000 live births (Posset et al, 2020; reviewed in Quinonez and Lee, 2022). Like other urea cycle disorders (UCDs), citrullinemia is characterized by hyperammonemia. Enzyme deficiency is also associated with high plasma levels of citrulline, glutamine, and orotic acid, with low arginine. Severe cases of citrullinemia result in encephalopathy, characterized by lethargy, vomiting, seizures, coma and death (reviewed in Matsumoto eta al, 2019; Schmitt Ribas et al, 2022; Quinonez and Lee, 2022).
Over 100 distinct disease-causing variants have been cataloged, including missense, nonsense, splice-site, deletions, and frameshift mutations (Diez-Fernandez et al, 2017). While some variants are identified in multiple cases, such as the most common allele G390R, others are private. Missense mutations typically disrupt enzyme folding or active‑site interactions (citrulline/aspartate binding), reducing catalytic activity.
Nonsense, frameshift, or splicing variants can truncate the protein or eliminate key exons, resulting in non-functional or absent enzyme (reviewed in Quinonez and Lee, 2022).
Literature References
PubMed ID Title Journal Year
33288448 Severity-adjusted evaluation of newborn screening on the metabolic disease course in individuals with cytosolic urea cycle disorders

Posset, R, Kölker, S, Gleich, F, Okun, JG, Gropman, AL, Nagamani, SCS, Scharre, S, Probst, J, Walter, ME, Hoffmann, GF, Garbade, SF, Zielonka, M, Urea Cycle Disorders Consortium, -, European registry and network for Intoxication type Metabolic Diseases (E-IMD) consortia study group, -

Mol Genet Metab 2020
27287393 Kinetic mutations in argininosuccinate synthetase deficiency: characterisation and in vitro correction by substrate supplementation

Diez-Fernandez, C, Wellauer, O, Gemperle, C, Rüfenacht, V, Fingerhut, R, Häberle, J

J Med Genet 2016
20301631 Citrullinemia Type I

Quinonez, SC, Lee, KN

2004
34665389 Hyperammonemia in Inherited Metabolic Diseases

Ribas, GS, Lopes, FF, Deon, M, Vargas, CR

Cell Mol Neurobiol 2022
28111830 Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations

Diez-Fernandez, C, Rüfenacht, V, Häberle, J

Hum Mutat 2017
8792870 Characterization of human wild-type and mutant argininosuccinate synthetase proteins expressed in bacterial cells

Shaheen, N, Kobayashi, K, Terazono, H, Fukushige, T, Horiuchi, M, Saheki, T

Enzyme Protein 1994
31110235 Urea cycle disorders-update

Matsumoto, S, Häberle, J, Kido, J, Mitsubuchi, H, Endo, F, Nakamura, K

J Hum Genet 2019
18473344 Investigation of citrullinemia type I variants by in vitro expression studies

Berning, C, Bieger, I, Pauli, S, Vermeulen, T, Vogl, T, Rummel, T, Höhne, W, Koch, HG, Rolinski, B, Gempel, K, Häberle, J

Hum Mutat 2008
Participants
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Disease
Name Identifier Synonyms
citrullinemia DOID:9273 deficiency of citrulline-aspartate ligase, ASS deficiency
Cross References
Mondo
Authored
Rothfels, K  (2025-07-02)
Created
Rothfels, K  (2025-06-12)
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