Alternative titles; symbols
HGNC Approved Gene Symbol: ARG1
SNOMEDCT: 23501004; ICD10CM: E72.21;
Cytogenetic location: 6q23.2 Genomic coordinates (GRCh38): 6:131,573,226-131,584,329 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q23.2 | Argininemia | 207800 | Autosomal recessive | 3 |
Arginase (EC 3.5.3.1) catalyzes the last step of the urea cycle. It is present in 2 forms, specified by separate gene loci, ARG1 and ARG2 (107830). The isoform encoded by ARG1, referred to as the liver, or A-I, isoform, contributes 98% of the arginase activity in liver but is also present in red cells. ARG2 encodes the mitochondrial, or A-II, isoform, which predominates in kidney.
Using a rat liver ARG1 cDNA clone to probe a human liver cDNA library, Haraguchi et al. (1987) isolated and characterized a cDNA corresponding to the ARG1 gene. The deduced 322-amino acid polypeptide has a molecular mass of 34.7 kD. A 1.6-kb mRNA was detected in liver. The amino acid sequence was 87% and 41% identical to those of the rat liver and yeast enzymes, respectively.
By immunologic studies, Spector et al. (1983) found that 90% of the arginase in red blood cell and liver was precipitated by the antibody, whereas only 50% of the arginase in kidney, brain, and the gastrointestinal tract reacted with it. Patients with arginase deficiency were found to have normal amounts of enzymatically inactive arginase in their red blood cells, whereas enzymatically active arginase was detected in kidney biopsies. The findings indicated 2 types of arginase protein defined by 2 genetic loci.
Colegio et al. (2014) showed that lactic acid produced by tumor cells, as a byproduct of aerobic or anaerobic glycolysis, has a critical function in signaling, through inducing the expression of vascular endothelial growth factor (VEGF; 192240) and the M2-like polarization of tumor-associated macrophages. The authors also demonstrated that this effect of lactic acid is mediated by hypoxia-inducible factor 1-alpha (HIF1A; 603348). Finally, they showed that the lactate-induced expression of arginase-1 by macrophages has an important role in tumor growth. Colegio et al. (2014) concluded that their findings identified a mechanism of communication between macrophages and their client cells, including tumor cells. This communication likely evolved to promote homeostasis in normal tissues but can also be engaged in tumors to promote their growth.
Poillet-Perez et al. (2018) demonstrated that host-specific deletion of Atg7 (608760) impairs the growth of multiple allografted tumors, although not all tumor lines were sensitive to host autophagy status. Loss of autophagy in the host was associated with a reduction in circulating arginine, and the sensitive tumor cell lines were arginine auxotrophs owing to the lack of expression of the enzyme argininosuccinate synthase 1. Serum proteomic analysis identified the arginine-degrading enzyme Arg1 in the circulation of Atg7-deficient hosts, and in vivo arginine metabolic tracing demonstrated that serum arginine was degraded to ornithine. ARG1 is predominantly expressed in the liver and can be released from hepatocytes into the circulation. Liver-specific deletion of Atg7 produced circulating Arg1, and reduced both serum arginine and tumor growth. Deletion of Atg5 (604261) in the host similarly regulated circulating arginine and suppressed tumorigenesis, which demonstrated that this phenotype is specific to autophagy function rather than to deletion of Atg7. Dietary supplementation of Atg7-deficient hosts with arginine partially restored levels of circulating arginine and tumor growth. Poillet-Perez et al. (2018) concluded that defective autophagy in the host leads to the release of ARG1 from the liver and the degradation of circulating arginine, which is essential for tumor growth, identifying a metabolic vulnerability of cancer.
Li et al. (2019) reported that the tumor suppressor p53 (191170) regulates ammonia metabolism by repressing the urea cycle. Through transcriptional downregulation of CPS1 (608307), OTC (300461), and ARG1, p53 suppresses ureagenesis and elimination of ammonia in vitro and in vivo, leading to the inhibition of tumor growth. Conversely, downregulation of these genes reciprocally activates p53 by MDM2 (164785)-mediated mechanism(s). Furthermore, the accumulation of ammonia causes a significant decline in mRNA translation of the polyamine biosynthetic rate-limiting enzyme ODC (ODC1; 165640), thereby inhibiting the biosynthesis of polyamine and cell proliferation. Li et al. (2019) conclude that together, their findings linked p53 to ureagenesis and ammonia metabolism, and further revealed a role for ammonia in controlling polyamine biosynthesis and cell proliferation.
Takiguchi et al. (1988) determined that the arginase gene contains 8 exons.
Sparkes et al. (1986) mapped the human liver arginase gene to chromosome 6q23 by a combination of somatic cell hybrid analysis and in situ hybridization.
In a Japanese girl with argininemia (207800), Haraguchi et al. (1990) found compound heterozygosity for 2 frameshift deletions in the ARG1 gene (608313.0001-608313.0002).
In patients with arginase deficiency, Grody et al. (1992) identified 2 mutations in the ARG1 gene (608313.0003-608313.0004). They concluded that arginase deficiency is heterogeneous at the genotypic level, generally encompassing a variety of point mutations rather than substantial structural gene deletions.
Diez-Fernandez et al. (2018) summarized data on all published and 12 novel ARG1 mutations, totaling 66 mutations from 112 patients. Missense mutations were the most common (30), followed by deletions (15), splicing (10), nonsense (7), duplications (2), insertions (1), and a translation initiation codon mutation. Most of the mutations (48) were found in single families, with 15 in up to 4 families and only 3 mutations (T134I; G235R, 608313.0006; and R21X, 608313.0012) found in 5, 14, and 16 families, respectively. The 30 missense mutations were distributed unevenly throughout the 8 exons, clustering in exons 1, 4, and 7. No clear genotype-phenotype correlation was observed. Even patients carrying homozygous 'devastating' mutations (e.g., nonsense and splicing) could develop later onset of the disease. Most ARG1 mutations led to late-onset disease; 6 mutations were associated with neonatal-onset disease (I8K, G106R, c.466-2A-G, c.77delA, c.262_265delAAGA (608313.0001), and c.647_648ins32).
Shih et al. (1972) found high blood arginine levels and low red cell arginase in Macaca fascicularis monkeys in the New England Regional Primate Center, indicating arginase deficiency. Terasaki et al. (1980) showed that the liver enzyme was identical in RBC-normal and RBC-deficient animals. Spector et al. (1985) confirmed the occurrence of red cell arginase deficiency in M. fascicularis trapped in the wild in various areas and showed that most lower animals (mouse, rat, rabbit, cat, dog) have a low level of red cell arginase. Baboon has a very low level, and orangutan and gorilla have relatively low levels. However, the level is high in the chimpanzee and in the cow. Spector et al. (1985) suggested that upregulation of red cell arginase in higher primates has evolved under positive selection pressure after having been extinguished in lower animals. The mechanism of the regulation may be in the gene itself or its immediate vicinity because it operates in cis and not in trans.
Iyer et al. (2002) found that Arg1-knockout mice were born in a nonmendelian ratio, but the genotypes were in Hardy-Weinberg equilibrium, suggesting sperm lacking Arg1 may be less fit to participate in fertilization. Knockout mice exhibited severe hyperammonemia and died between postnatal days 10 and 14. Livers of Arg1-deficient animals showed hepatocyte abnormalities, including cell swelling and inclusion. Plasma amino acid analysis showed that the mean arginine level in Arg1-knockout mice was 4-fold and 3-fold greater than in wildtype and heterozygous mice, respectively. Mean proline and ornithine levels were reduced, as were plasma concentrations of the branched-chain amino acids valine, isoleucine, and leucine. Glutamic acid, citrulline, and histidine levels were about 1.5-fold higher than in phenotypically normal animals. Iyer et al. (2002) concluded that Arg1-knockout mice duplicate several pathobiologic aspects of human argininemia.
Deignan et al. (2006) created mice with individual and combined knockout of Arg1 and Arg2. Arg1 knockout mice died by 14 days of age from hyperammonemia, while Arg2 knockout mice had no obvious phenotype. Arg1/Arg2 double-knockout mice exhibited the phenotype of the Arg1 knockout mice, with the additional absence of Arg2 not exacerbating the phenotype. Plasma amino acid measurements in the double-knockout mice showed arginine levels increased roughly 100-fold and ornithine decreased roughly 10-fold compared with wildtype. Arginine and ornithine levels were also altered in liver, kidney, brain, and small intestine in the double-knockout mice.
Deignan et al. (2008) stated that several guanidino compounds, which are direct or indirect metabolites of arginine, are elevated in the blood of uremic patients and in the plasma and cerebrospinal fluid of hyperargininemic patients. They assayed several guanidino compounds in arginase single- and double-knockout mice and found that alpha-keto-delta-guanidinovaleric acid, alpha-N-acetylarginine, and argininic acid were increased in brain tissue from Arg1 knockout and Arg1/Arg2 double-knockout animals. Several guanidino compounds were also elevated in plasma, liver, and kidney. Deignan et al. (2008) concluded that guanidino compounds may be the neuropathogenic agents responsible for complications in arginase deficiency.
Chikungunya virus (CHIKV) and Ross River virus (RRV) are arthritogenic alphaviruses. Stoermer et al. (2012) found that musculoskeletal inflammatory lesions in CHIKV- or RRV-infected mice, as well as macrophages present in those lesions, expressed high levels of Arg1 and Ym1 (Chi3l3). Arg1 and Ym1 are markers of alternatively activated immunoregulatory (M2) macrophages that have high phagocytic capacity and dampen inflammation. The macrophages of infected mice lacked Fizz1 (see RETNLB; 605645), which is also a marker of murine M2 macrophages. Mice lacking expression of Arg1 specifically in macrophages and neutrophils had high expression of Ym1, low expression of Fizz1, dramatically reduced viral loads, and decreased inflammatory pathology in musculoskeletal tissues at late times after RRV infection. Stoermer et al. (2012) concluded that CHIKV and RRV infection induce a unique myeloid cell activation program in inflamed musculoskeletal tissues that inhibits viral clearance and disease resolution in an ARG1-dependent manner.
In a Japanese girl with severe mental retardation, microcephaly, spastic tetraplegia, and intermittent convulsions caused by argininemia (207800), Haraguchi et al. (1990) found compound heterozygosity for 2 frameshift deletions in the ARG1 gene. One of these was a 4-base deletion at nucleotides 262-265 or 263-266 in exon 3, creating a stop codon at residue 132, and the other was a 1-base deletion at nucleotide 77 or 78 in exon 2 (608313.0002), creating a stop codon at residue 31. The 1-base deletion was inherited from the mother, whereas the 4-base deletion came from the father. The parents were not consanguineous.
For discussion of the 1-bp deletion in the ARG1 gene that was found in compound heterozygous state in a patient with microcephaly, spastic tetraplegia, and intermittent convulsions caused by argininemia (207800) by Haraguchi et al. (1990), see 608313.0001.
In a patient with arginase deficiency (207800), Grody et al. (1992) identified a homozygous mutation in the ARG1 gene, resulting in an arg291-to-ter (R291X) substitution.
In a patient with arginase deficiency (207800), Grody et al. (1992) identified a homozygous mutation in the ARG1 gene, resulting in a thr290-to-ser (T290S) substitution.
In a Japanese patient with argininemia (207800) manifested by psychomotor retardation and spastic tetraplegia, Uchino et al. (1992) identified compound heterozygous mutations in the ARG1 gene: a 365G-A transition resulting in a trp122-to-ter (W122X) substitution, and a gly235-to-arg (G235R; 608313.0006) substitution. The patient inherited the nonsense mutation from his mother and the missense mutation from his father.
In 2 Japanese patients with argininemia (207800), Uchino et al. (1992) identified a 703G-C transversion in exon 7 of the ARG1 gene, resulting in a gly235-to-arg (G235R) substitution. One patient was homozygous for the mutation and the other patient compound heterozygous for G235R and the trp122-to-ter mutation (W122X; 608313.0005).
In a Japanese patient with argininemia (207800), Uchino et al. (1992) identified a homozygous 1-bp deletion (842delC) in exon 8 of the ARG1 gene, resulting in a stop codon at residue 289.
In 3 related Puerto Rican patients with arginase deficiency (207800), followed from 1 to 21 years of age by Snyderman et al. (1979), Uchino et al. (1995) identified a 32T-C change in exon 1 of the ARG1 gene, resulting in an ile11-to-thr (I11T) substitution. The patients were compound heterozygous for the I11T mutation and a G235R mutation (608313.0006). Functional expression studies in E. coli showed that the I11T mutant protein activity was 12% of normal arginase. The mutant arginase proteins previously analyzed, such as G235R and W122X (608313.0005), had less than 1% of the control activity in vitro. Response to dietary therapy was good.
In a French Canadian patient with argininemia (207800), Uchino et al. (1995) identified compound heterozygous mutations in the ARG1 gene: a 413G-T transversion in exon 4, resulting in a gly138-to-val (G138V) substitution, and a donor splice site mutation (608313.0010).
This splice site mutation, involving nucleotide 57 of the ARG1 gene, was found by Uchino et al. (1995) in homozygous state in a French Canadian argininemia (207800) patient with consanguineous parents. The patient responded well to dietary therapy. The substitution violated the GT/AG rule for splice site junctions (Shapiro and Senapathy, 1987). In another French Canadian patient who showed slow improvement and did not have consanguineous parents, this mutation was found in compound heterozygous state with the G138V mutation (608313.0009).
In a Pakistani patient, born of consanguineous parents, with argininemia (207800), Uchino et al. (1995) identified an A-to-G substitution at the acceptor site of intron 4 of the ARG1 gene. The patient improved with dietary therapy.
In 4 unrelated Portuguese patients with argininemia (207800), Cardoso et al. (1999) identified a C-to-T transition in exon 2 of the ARG1 gene, resulting in an arg21-to-ter (R21X) substitution.
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Li, L., Mao, Y., Zhao, L., Li, L., Wu, J., Zhao, M., Du, W., Yu, L., Jiang, P. p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis. Nature 567: 253-256, 2019. Note: Erratum: Nature 569: E10, 2019. Electronic Article. [PubMed: 30842655] [Full Text: https://doi.org/10.1038/s41586-019-0996-7]
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