ASS1 variants don't synthesize arginosuccinate

Stable Identifier
R-HSA-9956517
Type
Reaction [transition]
Species
Homo sapiens
Compartment
cytosol
ReviewStatus
3/5
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ASS1 variants don't synthesize arginosuccinate
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Type 1 Citrullinemia (CTLN1) arises due to mutations in the ASS1 gene that encodes argininosuccinate synthase 1. This enzyme normally facilitates the ATP-dependent conversion of citrulline and aspartate to argininosuccinate, a critical step in the detoxification of nitrogen through urea formation.
The clinical features of CTLN1 include vomiting, lethargy, seizures, and potentially coma or death if untreated—particularly in neonates. Milder, later-onset forms may present with episodic symptoms due to partial enzyme activity (reviewed in Matsumoto et al, 2019; Schmitt-Ribas et al, 2022; Quinonez and Lee, 2022).
The following mutations are classified as pathogenic or likely pathogenic by ClinVar, and are listed as candidate or member alleles depending on the extent of their biochemical characterization:

Variants with decreased affinity for aspartate and compromised ASS1 activity:
Candidates:
ASS1 T284I (Engel et al, 2009; Diez-Fernandez et al, 2017)
ASS1 Y359D (Engel et al, 2009; Diez-Fernandez et al, 2017)

Members:
ASS1 T91P (Miller et al, 2014; Diez-Fernandez et al, 2016)
ASS1 A118T (Berning et al, 2008; Diez-Fernandez et al, 2016; Kobayashi et al, 1994)
ASS1 S180N (Kobayashi et al, 1990; Diez-Fernandez et al, 2016)
ASS1 R272C (Diez-Fernandez et al, 2016)
ASS1 R272H (Diez-Fernandez et al, 2016)
ASS1 R272L (Diez-Fernandez et al, 2016)
ASS1 R265C (Berning et al, 2008; Engel et al, 2009; Kimani et al, 2015; Diez-Fernandez et al, 2017)

Variants with decreased thermal stability and compromised ASS1 activity:
Candidates:
ASS1 V263M (Haberle et al, 2003; Berning et al, 2008)
ASS1 M302V (Berning 2008; Diez-Fernandez et al, 2017)

Members:
ASS1 T119I (Vilaseca et al, 2001; Diez-Fernandez et al, 2016)
ASS1 D124N (Kleijer et al, 2006; Diez-Fernandez et al, 2016)
ASS1 R127Q (Haberle et al, 2003; Engel et al, 2009; Diez-Fernandez et al, 2016)
ASS1 R157C (Gao et al, 2003; Miller et al, 2014; Diez-Fernandez et al, 2016)
ASS1 R157H (Kleijer et al, 2006; Kobayashi et al, 1990; Diez-Fernandez et al, 2016)
ASS1 S180I (Miller 2014; Diez-Fernandez et al, 2016)
ASS1 E191Q (Engel et al, 2009; Diez-Fernandez et al, 2016)

Other variants
Candidates:
ASS1 G14S (Kobayashi et al, 1990; Haberle et al, 2003)
ASS1 S18L (Kobayashi et al, 1991)
ASS1 R86C (Kobayashi et al, 1991)
ASS1 W179R (Haberle et al, 2002)
ASS1 R279* (Li et al, 2001)
ASS1 R304W (Kobayashi et al, 1990)
ASS1 K310Q (Whelan et al, 1976; Potter et al, 2004)
ASS1 G324S (Kobayashi et al, 1990)
ASS1 G362V (Haberle et al, 2002)
ASS1 G390R (Kobayashi et al, 1990)
Literature References
PubMed ID Title Journal Year
14680976 Mild citrullinemia in Caucasians is an allelic variant of argininosuccinate synthetase deficiency (citrullinemia type 1)

Häberle, J, Pauli, S, Schmidt, E, Schulze-Eilfing, B, Berning, C, Koch, HG

Mol Genet Metab 2003
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
934749 Citrullinemia: phenotypic variations

Whelan, DT, Brusso, T, Spate, M

Pediatrics 1976
19006241 Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene

Engel, K, Höhne, W, Häberle, J

Hum Mutat 2009
31110235 Urea cycle disorders-update

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

J Hum Genet 2019
11571557 A nonsense mutation is responsible for the RNA-negative phenotype in human citrullinaemia

Li, CM, Chao, HK, Liu, YF, Su, TS

Eur J Hum Genet 2001
11941481 Structure of the human argininosuccinate synthetase gene and an improved system for molecular diagnostics in patients with classical and mild citrullinemia

Häberle, J, Pauli, S, Linnebank, M, Kleijer, WJ, Bakker, HD, Wanders, RJ, Harms, E, Koch, HG

Hum Genet 2002
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
1943692 Additional mutations in argininosuccinate synthetase causing citrullinemia

Kobayashi, K, Rosenbloom, C, Beaudet, AL, O'Brien, WE

Mol Biol Med 1991
12815590 Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients

Gao, HZ, Kobayashi, K, Tabata, A, Tsuge, H, Iijima, M, Yasuda, T, Kalkanoglu, HS, Dursun, A, Tokatli, A, Coskun, T, Trefz, FK, Skladal, D, Mandel, H, Seidel, J, Kodama, S, Shirane, S, Ichida, T, Makino, S, Yoshino, M, Kang, JH, Mizuguchi, M, Barshop, BA, Fuchinoue, S, Seneca, S, Zeesman, S, Knerr, I, Rodés, M, Wasant, P, Yoshida, I, De Meirleir, L, Abdul Jalil, M, Begum, L, Horiuchi, M, Katunuma, N, Nakagawa, S, Saheki, T

Hum Mutat 2003
16475226 Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia

Kleijer, WJ, Garritsen, VH, van der Sterre, ML, Berning, C, Häberle, J, Huijmans, JG

Prenat Diagn 2006
24889030 Improved standards for prenatal diagnosis of citrullinemia

Miller, MJ, Soler-Alfonso, CR, Grund, JE, Fang, P, Sun, Q, Elsea, SH, Sutton, VR

Mol Genet Metab 2014
2358466 Heterogeneity of mutations in argininosuccinate synthetase causing human citrullinemia

Kobayashi, K, Jackson, MJ, Tick, DB, O'Brien, WE, Beaudet, AL

J Biol Chem 1990
15266621 Pregnancy in a healthy woman with untreated citrullinemia

Potter, MA, Zeesman, S, Brennan, B, Kobayashi, K, Gao, HZ, Tabata, A, Saheki, T, Whelan, DT

Am J Med Genet A 2004
11708871 Phenotype and genotype heterogeneity in Mediterranean citrullinemia

Vilaseca, MA, Kobayashi, K, Briones, P, Lambruschini, N, Campistol, J, Tabata, A, Alomar, A, Rodés, M, Lluch, M, Saheki, T

Mol Genet Metab 2001
25179242 Functional analysis of novel splicing and missense mutations identified in the ASS1 gene in classical citrullinemia patients

Kimani, JK, Wei, T, Chol, K, Li, Y, Yu, P, Ye, S, Huang, X, Qi, M

Clin Chim Acta 2015
Participants
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Catalyst Activity

argininosuccinate synthase activity of ASS1 variant tetramer:NMRAL1 dimer:NADPH [cytosol]

Physical Entity
ASS1 variant tetramer:NMRAL1 dimer:NADPH [cytosol] (Homo sapiens)
Activity
argininosuccinate synthase activity (GO:0004055)
Normal reaction
ASS1 tetramer:NMRAL1 dimer:NADPH transforms L-Asp and L-Cit to ARSUA (Homo sapiens)
Functional status

Loss of function of ASS1 variant tetramer:NMRAL1 dimer:NADPH [cytosol]

Normal Entity
Disease Entity
Status
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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