Alternative titles; symbols
HGNC Approved Gene Symbol: ASL
SNOMEDCT: 41013004;
Cytogenetic location: 7q11.21 Genomic coordinates (GRCh38) : 7:66,075,819-66,093,576 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q11.21 | Argininosuccinic aciduria | 207900 | Autosomal recessive | 3 |
The ASL gene encodes the subunit of argininosuccinate lyase (EC 4.3.2.1) is a urea cycle enzyme that catalyzes the cleavage of argininosuccinate to fumarate and arginine, an essential step in the process of detoxification of ammonia via the urea cycle (O'Brien et al., 1986).
Using antibodies specific for argininosuccinate lyase to screen a human liver cDNA library, O'Brien et al. (1986) isolated a cDNA corresponding to the human ASL gene. The cDNA encodes a deduced protein of 463 amino acids with a predicted molecular mass of 52 kD, and the active enzyme is a homotetramer. The amino acid sequence of the human enzyme shows 56% homology to the yeast enzyme. Matuo et al. (1988) isolated clones of human ASL cDNA and determined the nucleotide sequence. They corrected some minor errors in the sequence reported by O'Brien et al. (1986).
Abramson et al. (1991) found that the DNA sequences encoded by exon 7 were deleted in approximately 5 to 10% of the mature mRNA in all tissue sources examined, suggesting alternative splicing. Walker et al. (1990) presented evidence for an alternatively spliced ASL transcript in which exon 2 is removed.
Abramson et al. (1991) demonstrated that the ASL gene contains 16 exons. The exon structure of the gene is identical to that of the rat and similar to that of the delta-crystallin genes in the chicken.
Linnebank et al. (2002) completed the structure and sequence of the ASL gene and determined that it has 17 exons. The first, exon zero (0), codes only for the 5-untranslated region.
Zhao et al. (2010) showed that lysine acetylation is a prevalent modification in enzymes that catalyze intermediate metabolism in the human liver. Virtually every enzyme in glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, the urea cycle, fatty acid metabolism, and glycogen metabolism was found to be acetylated in human liver tissue. The concentration of metabolic fuels, such as glucose, amino acids, and fatty acids, influenced the acetylation status of metabolic enzymes. Acetylation activated enoyl-coenzyme A hydratase/3-hydroxyacyl-coenzyme A dehydrogenase (607037) in fatty acid oxidation and malate dehydrogenase (see 154200) in the TCA cycle, inhibited argininosuccinate lyase in the urea cycle, and destabilized phosphoenolpyruvate carboxykinase (261680) in gluconeogenesis. Zhao et al. (2010) concluded that acetylation plays a major role in metabolic regulation.
Naylor et al. (1978) assigned the gene for ASL to chromosome 7. By analysis of genomic DNA from hamster-human cell hybrids, O'Brien et al. (1986) assigned the ASL gene to chromosome 7. By in situ hybridization, Todd et al. (1989) mapped ASL to 7cen-q11.2.
Pseudogene
O'Brien et al. (1986) found that the 5-prime end of the ASL cDNA was also hybridized to a site on chromosome 22, which the authors assumed to be a pseudogene. Todd et al. (1989) also detected a sequence on chromosome 22.
Linnebank et al. (2002) identified a complete ASL homolog on chromosome 22q11.2 and stated that this so-called pseudogene is a regular gene with a promoter region, a poly-A signal, and 11 exons containing a typical initial exon and a terminal exon. The predicted coding sequence of the pseudogene shared more than 0.4 kb high homology with ASL cDNA. A GenBank search with a predicted cDNA revealed that the pseudogene might encode immunoglobulin-lambda-like mRNA (IGLL1; 146770).
Trevisson et al. (2007) identified a second ASL pseudogene located on chromosome 7 about 3 Mb upstream of the ASL gene, close to the centromere. There was no evidence of expression of this second pseudogene.
In fibroblasts from a patient with ASL deficiency (207900) whose parents were consanguineous, Walker et al. (1990) identified a homozygous mutation in the ASL gene (608310.0001).
In 27 unrelated patients with ASL deficiency, Linnebank et al. (2002) identified 23 different mutations, 19 novel, in the ASL gene. Fifteen of the 54 alleles had an IVS5+1G-A splice site mutation (608310.0003).
In 5 patients with a biochemical variant of ASL deficiency in which there was residual enzyme activity and mild clinical symptoms, Kleijer et al. (2002) identified several mutations in the ASL gene. R385C (608310.0004), V178M (608310.0005), and R379C (608310.0006) were detected in homozygous states, whereas 1 patient was compound heterozygous for 2 known mutations, including Q286R (608310.0002). Prenatal diagnosis was successfully performed in 3 of the families.
Trevisson et al. (2007) identified 16 different mutations in the ASL gene, including 14 novel mutations, in 12 Italian patients from 10 families with ASL deficiency. All patients tested, except 1, had less than 5% residual enzyme activity. Mutations were scattered throughout the gene, but there were no genotype/phenotype correlations.
AlTassan et al. (2018) identified homozygous mutations in the ASL gene in 35 Arab patients with ASL deficiency, including 26 patients with the same nonsense mutation (Q354X; 608310.0007), 7 with an R186W missense mutation, and 2 with different splice site mutations. All of the patients had elevated plasma and urine argininosuccinic acid and plasma citrulline.
Piatigorsky et al. (1988) demonstrated an extraordinary similarity between the structural protein delta-crystallin of the lens of the duck and the enzyme argininosuccinate lyase. Delta-crystallin is the dominant crystallin in the lenses of birds and reptiles, but is absent from lenses of mammals. It appears that birds, being uricotelic, have relatively little use for the metabolic enzyme but use the protein as a structural element by producing very large amounts. Southern blot hybridization experiments with chicken delta-crystallin cDNA and human ASL cDNA, coupled with enzymatic tests, provided strong evidence that the crystallin and the enzyme share genes in an unusual evolutionary strategy. 'Gene sharing' was the designation given this phenomenon, i.e., when 2 distinct protein phenotypes are produced by the same transcriptional unit. Once an enzyme has been recruited to serve as a structural protein in lens, in addition to its conserved role in metabolism, it is subject to at least 2 independent sets of evolutionary pressure. This may lead to sequence modifications that enhance its function as a crystallin, or gene duplication may take place with subsequent partial separation of function (Piatigorsky and Wistow, 1991).
Erez et al. (2011) created a hypomorphic mouse model of ASL deficiency and showed that this mouse has a distinct phenotype of multiorgan dysfunction and nitric oxide deficiency. Administration of nitrite, which can be converted into nitric oxide in vivo, rescued the manifestations of nitric oxide deficiency in hypomorphic Asl mice, and a nitric oxide synthase-independent nitric oxide donor restored nitric oxide-dependent vascular reactivity in humans with ASL deficiency. Mechanistic studies showed that ASL has a structural function in addition to the catalytic activity, by which it contributes to the formation of a multiprotein complex required for nitric oxide production. Erez et al. (2011) concluded their data demonstrated an unappreciated role for ASL in nitric oxide synthase function and nitric oxide homeostasis.
Nagamani et al. (2012) performed liver-directed gene therapy in a mouse model of argininosuccinic aciduria (ASA) to distinguish the relative contributions of the hepatic urea cycle defect from those of the nitric oxide deficiency in the ASA phenotype. Whereas the gene therapy corrected the ureagenesis defect, the systemic hypertension in mice could be corrected by treatment with an exogenous NO source.
In fibroblasts from a patient with late-onset ASL deficiency (207900) who was the product of a consanguineous mating, Walker et al. (1990) identified a homozygous 283C-T change in exon 3 of the ASL gene, resulting in an arg95-to-cys (R95C) substitution within a 13-residue stretch that is identical in yeast and human ASL. Enzyme activity of the mutant protein was about 1%.
In a cell line from a patient with neonatal-onset of argininosuccinic aciduria (207900) whose parents were consanguineous, Walker et al. (1990) identified an 857A-G transition in exon 11 of the ASL gene, resulting in a gln286-to-arg (Q286R) substitution. The mutation occurred in a region of 18 amino acids identical in yeast and human ASL, and in a region of 10 amino acids highly conserved in the family of class II fumarases. The mutant enzyme retained less than 3% of residual ASL activity.
Linnebank et al. (2002) found that 15 of 54 ASL deficiency (207900)-related alleles had an IVS5+1G-A splice site mutation in the ASL gene that resulted in the deletion of 21 amino acids.
In 2 patients from a family with variable age of onset of ASL deficiency (207900) and considerable residual ASL activity, Kleijer et al. (2002) identified a homozygous 1153C-T transition in the ASL gene, resulting in an arg385-to-cys (R385C) substitution.
In a patient from a family with variable age of onset of ASL deficiency (207900) and considerable residual ASL activity, Kleijer et al. (2002) identified a homozygous 532G-A transition in the ASL gene, resulting in a val178-to-met (V178M) substitution.
In a patient from a family with variable age of onset of ASL deficiency (207900) and considerable residual ASL activity, Kleijer et al. (2002) identified a homozygous 1135C-T transition in the ASL gene, resulting in an arg379-to-cys (R379C) substitution.
In 26 of 35 Saudi Arabian patients with argininosuccinic aciduria (207900), AlTassan et al. (2018) identified homozygosity for a c.1060C-T transition in the ASL gene, predicted to result in a gln354-to-ter (Q354X) substitution, suggesting that it is a founder mutation in this population.
Abramson, R. D., Barbosa, P., Kalumuck, K., O'Brien, W. E. Characterization of the human argininosuccinate lyase gene and analysis of exon skipping. Genomics 10: 126-132, 1991. [PubMed: 2045097] [Full Text: https://doi.org/10.1016/0888-7543(91)90492-w]
AlTassan, R., Bubshait, D., Imtiaz, F., Rahbeeni, Z. A retrospective biochemical, molecular, and neurocognitive review of Saudi patients with argininosuccinic aciduria. Europ. J. Med. Genet. 61: 307-311, 2018. [PubMed: 29326055] [Full Text: https://doi.org/10.1016/j.ejmg.2018.01.007]
Erez, A., Nagamani, S. C. S., Shchelochkov, O. A., Premkumar, M. H., Campeau, P. M., Chen, Y., Garg, H. K., Li, L., Mian, A., Bertin, T. K., Black, J. O., Zeng, H., and 10 others. Requirement of argininosuccinate lyase for systemic nitric oxide production. Nature Med. 17: 1619-1626, 2011. [PubMed: 22081021] [Full Text: https://doi.org/10.1038/nm.2544]
Kleijer, W. J., Garritsen, V. H., Linnebank, M., Mooyer, P., Huijmans, J. G. M., Mustonen, A., Simola, K. O. J., Arslan-Kirchner, M., Battini, R., Briones, P., Cardo, E., Mandel, H., Tschiedel, E., Wanders, R. J. A., Koch, H. G. Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in 5 unrelated families. J. Inherit. Metab. Dis. 25: 399-410, 2002. [PubMed: 12408190] [Full Text: https://doi.org/10.1023/a:1020108002877]
Linnebank, M., Tschiedel, E., Haberle, J., Linnebank, A., Willenbring, H., Kleijer, W. J., Koch, H. G. Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene. Hum. Genet. 111: 350-359, 2002. [PubMed: 12384776] [Full Text: https://doi.org/10.1007/s00439-002-0793-4]
Matuo, S., Tatsuno, M., Kobayashi, K., Saheki, T., Miyata, T., Iwanaga, S., Amaya, Y., Mori, M. Isolation of cDNA clones of human argininosuccinate lyase and corrected amino acid sequence. FEBS Lett. 234: 395-399, 1988. [PubMed: 3391281] [Full Text: https://doi.org/10.1016/0014-5793(88)80124-8]
Nagamani, S. C. S., Campeau, P. M., Shchelochkov, O. A., Premkumar, M. H., Guse, K., Brunetti-Pierri, N., Chen, Y., Sun, Q., Tang, Y., Palmer, D., Reddy, A. K., Li, L., and 9 others. Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. Am. J. Hum. Genet. 90: 836-846, 2012. [PubMed: 22541557] [Full Text: https://doi.org/10.1016/j.ajhg.2012.03.018]
Naylor, S. L., Klebe, R. J., Shows, T. B. Argininosuccinic aciduria: assignment of the argininosuccinate lyase gene to the pter-q22 region of human chromosome 7 by bioautography. Proc. Nat. Acad. Sci. 75: 6159-6162, 1978. [PubMed: 282632] [Full Text: https://doi.org/10.1073/pnas.75.12.6159]
O'Brien, W. E., McInnes, R., Kalumuck, K., Adcock, M. Cloning and sequence analysis of cDNA for human argininosuccinate lyase. Proc. Nat. Acad. Sci. 83: 7211-7215, 1986. [PubMed: 3463959] [Full Text: https://doi.org/10.1073/pnas.83.19.7211]
Piatigorsky, J., O'Brien, W. E., Norman, B. L., Kalumuck, K., Wistow, G. J., Borras, T., Nickerson, J. M., Wawrousek, E. F. Gene sharing by delta-crystallin and argininosuccinate lyase. Proc. Nat. Acad. Sci. 85: 3479-3483, 1988. [PubMed: 3368457] [Full Text: https://doi.org/10.1073/pnas.85.10.3479]
Piatigorsky, J., Wistow, G. The recruitment of crystallins: new functions precede gene duplication. Science 252: 1078-1079, 1991. [PubMed: 2031181] [Full Text: https://doi.org/10.1126/science.252.5009.1078]
Todd, S., McGill, J. R., McCombs, J. L., Moore, C. M., Weider, I., Naylor, S. L. cDNA sequence, interspecies comparison and gene mapping analysis of argininosuccinate lyase. Genomics 4: 53-59, 1989. [PubMed: 2644168] [Full Text: https://doi.org/10.1016/0888-7543(89)90314-5]
Trevisson, E., Salviati, L., Baldoin, M. C., Toldo, I., Casarin, A., Sacconi, S., Cesaro, L., Basso, G., Burlina, A. B. Argininosuccinate lyase deficiency: mutational spectrum in Italian patients and identification of a novel ASL pseudogene. Hum. Mutat. 28: 694-702, 2007. [PubMed: 17326097] [Full Text: https://doi.org/10.1002/humu.20498]
Walker, D. C., McCloskey, D. A., Simard, L. R., McInnes, R. R. Molecular analysis of human argininosuccinate lyase (ASAL): mutant characterization and alternate splicing of the active site. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A227 only, 1989.
Walker, D. C., McCloskey, D. A., Simard, L. R., McInnes, R. R. Identification of a mutation frequently involved in interallelic complementation at the human argininosuccinic acid lyase locus. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A169 only, 1990.
Walker, D. C., McCloskey, D. A., Simard, L. R., McInnes, R. R. Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region. Proc. Nat. Acad. Sci. 87: 9625-9629, 1990. [PubMed: 2263616] [Full Text: https://doi.org/10.1073/pnas.87.24.9625]
Zhao, S., Xu, W., Jiang, W., Yu, W., Lin, Y., Zhang, T., Yao, J., Zhou, L., Zeng, Y., Li, H., Li, Y., Shi, J., and 10 others. Regulation of cellular metabolism by protein lysine acetylation. Science 327: 1000-1004, 2010. [PubMed: 20167786] [Full Text: https://doi.org/10.1126/science.1179689]