RBCC Red Blood Cell Collection

ARG1 [Confidence: high (present in two of the MS resources)]
Arginase-1; 3.5.3.1 (Liver-type arginase; Type I arginase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00291560
IPI00291560 Splice isoform 1 or 2 of P05089 Arginase 1 Splice isoform 1 or 2 of P05089 Arginase 1 membrane n/a 6 3 1 5 n/a 3 2 1 n/a n/a n/a n/a n/a n/a n/a n/a 9 6 7 cytoplasmic n/a found at its expected molecular weight found at molecular weight

Comments
Isoform P05089-2 was detected.

UniProt P05089
ID ARGI1_HUMAN Reviewed; 322 AA.
AC P05089; A6NEA0; Q5JWT5; Q5JWT6; Q8TE72; Q9BS50;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 11-JAN-2001, sequence version 2.
DT 22-JAN-2014, entry version 170.
DE RecName: Full=Arginase-1;
DE EC=3.5.3.1;
DE AltName: Full=Liver-type arginase;
DE AltName: Full=Type I arginase;
GN Name=ARG1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=3540966; DOI=10.1073/pnas.84.2.412;
RA Haraguchi Y., Takiguchi M., Amaya Y., Kawamoto S., Matsuda I.,
RA Mori M.;
RT "Molecular cloning and nucleotide sequence of cDNA for human liver
RT arginase.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:412-415(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Blood;
RX PubMed=3174433; DOI=10.1093/nar/16.18.8789;
RA Takiguchi M., Haraguchi Y., Mori M.;
RT "Human liver-type arginase gene: structure of the gene and analysis of
RT the promoter region.";
RL Nucleic Acids Res. 16:8789-8802(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Erythroblast;
RA Lee Y.T., Miller J.L.;
RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E.,
RA Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S.,
RA Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J.,
RA Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P.,
RA Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E.,
RA Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A.,
RA Frankland J., French L., Garner P., Garnett J., Ghori M.J.,
RA Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M.,
RA Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S.,
RA Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R.,
RA Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E.,
RA Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A.,
RA Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M.,
RA Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K.,
RA McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T.,
RA Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R.,
RA Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W.,
RA Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M.,
RA Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L.,
RA Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J.,
RA Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L.,
RA Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W.,
RA Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A.,
RA Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Liver, and Skeletal muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-13, AND SUBUNIT.
RC TISSUE=Liver;
RX PubMed=2241902;
RA Ikemoto M., Tabata M., Miyake T., Kono T., Mori M., Totani M.,
RA Murachi T.;
RT "Expression of human liver arginase in Escherichia coli. Purification
RT and properties of the product.";
RL Biochem. J. 270:697-703(1990).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (1.29 ANGSTROMS) IN COMPLEX WITH MANGANESE IONS
RP AND THE SYNTHETIC INHIBITOR 2(S)-AMINO-6-BORONOHEXANOIC ACID,
RP SUBCELLULAR LOCATION, AND SUBUNIT.
RX PubMed=16141327; DOI=10.1073/pnas.0504027102;
RA Di Costanzo L., Sabio G., Mora A., Rodriguez P.C., Ochoa A.C.,
RA Centeno F., Christianson D.W.;
RT "Crystal structure of human arginase I at 1.29-A resolution and
RT exploration of inhibition in the immune response.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:13058-13063(2005).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) IN COMPLEX WITH MANGANESE IONS
RP AND THE SYNTHETIC INHIBITOR 2(S)-AMINO-6-BORONOHEXANOIC ACID, AND MASS
RP SPECTROMETRY.
RX PubMed=17562323; DOI=10.1016/j.abb.2007.04.036;
RA Di Costanzo L., Moulin M., Haertlein M., Meilleur F.,
RA Christianson D.W.;
RT "Expression, purification, assay, and crystal structure of
RT perdeuterated human arginase I.";
RL Arch. Biochem. Biophys. 465:82-89(2007).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) IN COMPLEX WITH MANGANESE IONS
RP AND THIOSEMICARBAZIDE, AND SUBUNIT.
RX PubMed=17469833; DOI=10.1021/ja071567j;
RA Di Costanzo L., Pique M.E., Christianson D.W.;
RT "Crystal structure of human arginase I complexed with
RT thiosemicarbazide reveals an unusual thiocarbonyl mu-sulfide ligand in
RT the binuclear manganese cluster.";
RL J. Am. Chem. Soc. 129:6388-6389(2007).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (1.51 ANGSTROMS) IN COMPLEX WITH MANGANESE IONS
RP AND THE SYNTHETIC INHIBITOR (2S)-2-AMINO-7,8-EPOXYOCTANOIC ACID.
RX PubMed=18802628; DOI=10.1039/b811797g;
RA Zakharian T.Y., Di Costanzo L., Christianson D.W.;
RT "Synthesis of (2S)-2-amino-7,8-epoxyoctanoic acid and structure of its
RT metal-bridging complex with human arginase I.";
RL Org. Biomol. Chem. 6:3240-3243(2008).
RN [13]
RP VARIANT ARGIN ARG-235.
RX PubMed=1463019;
RA Uchino T., Haraguchi Y., Aparicio J.M., Mizutani N., Higashikawa M.,
RA Naitoh H., Mori M., Matsuda I.;
RT "Three novel mutations in the liver-type arginase gene in three
RT unrelated Japanese patients with argininemia.";
RL Am. J. Hum. Genet. 51:1406-1412(1992).
RN [14]
RP VARIANT SER-290.
RX PubMed=1598908;
RA Grody W.W., Klein D., Dodson A.E., Kern R.M., Wissmann P.B.,
RA Goodman B.K., Bassand P., Marescau B., Kang S.-S., Leonard J.V.,
RA Cederbaum S.D.;
RT "Molecular genetic study of human arginase deficiency.";
RL Am. J. Hum. Genet. 50:1281-1290(1992).
RN [15]
RP VARIANTS ARGIN THR-11 AND VAL-138.
RX PubMed=7649538; DOI=10.1007/BF00210403;
RA Uchino T., Snyderman S.E., Lambert M., Qureshi I.A., Shapira S.K.,
RA Sansaricq C., Smit L.M.E., Jakobs C., Matsuda I.;
RT "Molecular basis of phenotypic variation in patients with
RT argininemia.";
RL Hum. Genet. 96:255-260(1995).
CC -!- CATALYTIC ACTIVITY: L-arginine + H(2)O = L-ornithine + urea.
CC -!- COFACTOR: Binds 2 manganese ions per subunit.
CC -!- PATHWAY: Nitrogen metabolism; urea cycle; L-ornithine and urea
CC from L-arginine: step 1/1.
CC -!- SUBUNIT: Homotrimer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P05089-1; Sequence=Displayed;
CC Name=2; Synonyms=Erythroid variant;
CC IsoId=P05089-2; Sequence=VSP_009330;
CC Note=May be due to a competing acceptor splice site. No
CC experimental confirmation available;
CC Name=3;
CC IsoId=P05089-3; Sequence=VSP_009331;
CC -!- INDUCTION: By arginine or homoarginine.
CC -!- DISEASE: Argininemia (ARGIN) [MIM:207800]: A rare autosomal
CC recessive disorder of the urea cycle. Arginine is elevated in the
CC blood and cerebrospinal fluid, and periodic hyperammonemia occurs.
CC Clinical manifestations include developmental delay, seizures,
CC mental retardation, hypotonia, ataxia and progressive spastic
CC quadriplegia. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the arginase family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ARG1";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Arginase entry;
CC URL="http://en.wikipedia.org/wiki/Arginase";
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DR EMBL; M14502; AAA51776.1; -; mRNA.
DR EMBL; X12662; CAA31188.1; -; Genomic_DNA.
DR EMBL; X12663; CAA31188.1; JOINED; Genomic_DNA.
DR EMBL; X12664; CAA31188.1; JOINED; Genomic_DNA.
DR EMBL; X12665; CAA31188.1; JOINED; Genomic_DNA.
DR EMBL; X12666; CAA31188.1; JOINED; Genomic_DNA.
DR EMBL; X12667; CAA31188.1; JOINED; Genomic_DNA.
DR EMBL; X12668; CAA31188.1; JOINED; Genomic_DNA.
DR EMBL; X12669; CAA31188.1; JOINED; Genomic_DNA.
DR EMBL; AY074488; AAL71547.1; -; mRNA.
DR EMBL; BT006741; AAP35387.1; -; mRNA.
DR EMBL; AL121575; CAB92071.1; -; Genomic_DNA.
DR EMBL; AL121575; CAI23317.1; -; Genomic_DNA.
DR EMBL; AL121575; CAI23318.1; -; Genomic_DNA.
DR EMBL; BC005321; AAH05321.1; -; mRNA.
DR EMBL; BC020653; AAH20653.1; -; mRNA.
DR PIR; S02132; A26370.
DR RefSeq; NP_000036.2; NM_000045.3.
DR RefSeq; NP_001231367.1; NM_001244438.1.
DR UniGene; Hs.440934; -.
DR PDB; 1WVA; X-ray; 1.94 A; A/B=1-322.
DR PDB; 1WVB; X-ray; 2.30 A; A/B=1-322.
DR PDB; 2AEB; X-ray; 1.29 A; A/B=1-322.
DR PDB; 2PHA; X-ray; 1.90 A; A/B=1-322.
DR PDB; 2PHO; X-ray; 1.95 A; A/B=1-322.
DR PDB; 2PLL; X-ray; 1.90 A; A/B=1-322.
DR PDB; 2ZAV; X-ray; 1.70 A; A/B=1-322.
DR PDB; 3DJ8; X-ray; 1.51 A; A/B=1-322.
DR PDB; 3E6K; X-ray; 2.10 A; A/B=1-322.
DR PDB; 3E6V; X-ray; 1.72 A; A/B=1-322.
DR PDB; 3F80; X-ray; 1.60 A; A/B=1-322.
DR PDB; 3GMZ; X-ray; 1.43 A; A/B=1-322.
DR PDB; 3GN0; X-ray; 1.70 A; A/B=1-322.
DR PDB; 3KV2; X-ray; 1.55 A; A/B=1-322.
DR PDB; 3LP4; X-ray; 1.90 A; A/B=1-322.
DR PDB; 3LP7; X-ray; 2.04 A; A/B=1-322.
DR PDB; 3MFV; X-ray; 1.90 A; A/B=1-322.
DR PDB; 3MFW; X-ray; 1.47 A; A/B=1-322.
DR PDB; 3MJL; X-ray; 1.90 A; A/B=1-322.
DR PDB; 3SJT; X-ray; 1.60 A; A/B=1-322.
DR PDB; 3SKK; X-ray; 1.70 A; A/B=1-322.
DR PDB; 3TF3; X-ray; 1.64 A; A/B=1-322.
DR PDB; 3TH7; X-ray; 2.10 A; A/B=1-322.
DR PDB; 3THE; X-ray; 1.97 A; A/B=1-322.
DR PDB; 3THH; X-ray; 1.85 A; A/B=1-322.
DR PDB; 3THJ; X-ray; 1.50 A; A/B=1-322.
DR PDB; 4FCI; X-ray; 1.82 A; A/B=1-322.
DR PDB; 4FCK; X-ray; 1.90 A; A/B=1-322.
DR PDB; 4GSM; X-ray; 1.70 A; A/B=1-322.
DR PDB; 4GSV; X-ray; 1.48 A; A/B=1-322.
DR PDB; 4GSZ; X-ray; 2.20 A; A/B=1-322.
DR PDB; 4GWC; X-ray; 1.90 A; A/B=1-322.
DR PDB; 4GWD; X-ray; 1.53 A; A/B=1-322.
DR PDB; 4HWW; X-ray; 1.30 A; A/B=5-318.
DR PDB; 4HXQ; X-ray; 1.45 A; A/B=5-318.
DR PDB; 4IE1; X-ray; 2.00 A; A/B=5-318.
DR PDBsum; 1WVA; -.
DR PDBsum; 1WVB; -.
DR PDBsum; 2AEB; -.
DR PDBsum; 2PHA; -.
DR PDBsum; 2PHO; -.
DR PDBsum; 2PLL; -.
DR PDBsum; 2ZAV; -.
DR PDBsum; 3DJ8; -.
DR PDBsum; 3E6K; -.
DR PDBsum; 3E6V; -.
DR PDBsum; 3F80; -.
DR PDBsum; 3GMZ; -.
DR PDBsum; 3GN0; -.
DR PDBsum; 3KV2; -.
DR PDBsum; 3LP4; -.
DR PDBsum; 3LP7; -.
DR PDBsum; 3MFV; -.
DR PDBsum; 3MFW; -.
DR PDBsum; 3MJL; -.
DR PDBsum; 3SJT; -.
DR PDBsum; 3SKK; -.
DR PDBsum; 3TF3; -.
DR PDBsum; 3TH7; -.
DR PDBsum; 3THE; -.
DR PDBsum; 3THH; -.
DR PDBsum; 3THJ; -.
DR PDBsum; 4FCI; -.
DR PDBsum; 4FCK; -.
DR PDBsum; 4GSM; -.
DR PDBsum; 4GSV; -.
DR PDBsum; 4GSZ; -.
DR PDBsum; 4GWC; -.
DR PDBsum; 4GWD; -.
DR PDBsum; 4HWW; -.
DR PDBsum; 4HXQ; -.
DR PDBsum; 4IE1; -.
DR ProteinModelPortal; P05089; -.
DR SMR; P05089; 5-318.
DR IntAct; P05089; 8.
DR MINT; MINT-3974693; -.
DR STRING; 9606.ENSP00000357066; -.
DR BindingDB; P05089; -.
DR ChEMBL; CHEMBL1075097; -.
DR DrugBank; DB00129; L-Ornithine.
DR PhosphoSite; P05089; -.
DR DMDM; 12230985; -.
DR PaxDb; P05089; -.
DR PRIDE; P05089; -.
DR DNASU; 383; -.
DR Ensembl; ENST00000356962; ENSP00000349446; ENSG00000118520.
DR Ensembl; ENST00000368087; ENSP00000357066; ENSG00000118520.
DR Ensembl; ENST00000476845; ENSP00000417694; ENSG00000118520.
DR GeneID; 383; -.
DR KEGG; hsa:383; -.
DR UCSC; uc003qco.2; human.
DR CTD; 383; -.
DR GeneCards; GC06P131936; -.
DR HGNC; HGNC:663; ARG1.
DR HPA; CAB009434; -.
DR HPA; CAB056159; -.
DR HPA; HPA003595; -.
DR HPA; HPA024006; -.
DR MIM; 207800; phenotype.
DR MIM; 608313; gene.
DR neXtProt; NX_P05089; -.
DR Orphanet; 90; Argininemia.
DR PharmGKB; PA24947; -.
DR eggNOG; COG0010; -.
DR HOGENOM; HOG000204319; -.
DR HOVERGEN; HBG003030; -.
DR KO; K01476; -.
DR OMA; DYGDLPF; -.
DR OrthoDB; EOG747PJ5; -.
DR BioCyc; MetaCyc:HS04231-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P05089; -.
DR UniPathway; UPA00158; UER00270.
DR EvolutionaryTrace; P05089; -.
DR GenomeRNAi; 383; -.
DR NextBio; 1603; -.
DR PRO; PR:P05089; -.
DR Bgee; P05089; -.
DR CleanEx; HS_ARG1; -.
DR Genevestigator; P05089; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0043005; C:neuron projection; IEA:Ensembl.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0004053; F:arginase activity; EXP:Reactome.
DR GO; GO:0030145; F:manganese ion binding; IEA:Ensembl.
DR GO; GO:0006527; P:arginine catabolic process; TAS:ProtInc.
DR GO; GO:0071549; P:cellular response to dexamethasone stimulus; IEA:Ensembl.
DR GO; GO:0071377; P:cellular response to glucagon stimulus; IEA:Ensembl.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEA:Ensembl.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0071560; P:cellular response to transforming growth factor beta stimulus; IEA:Ensembl.
DR GO; GO:0032964; P:collagen biosynthetic process; IEA:Ensembl.
DR GO; GO:0001889; P:liver development; IEA:Ensembl.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0060056; P:mammary gland involution; IEA:Ensembl.
DR GO; GO:0060135; P:maternal process involved in female pregnancy; IEA:Ensembl.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IEA:Ensembl.
DR GO; GO:0070207; P:protein homotrimerization; IEA:Ensembl.
DR GO; GO:0010963; P:regulation of L-arginine import; IEA:Ensembl.
DR GO; GO:0014075; P:response to amine stimulus; IEA:Ensembl.
DR GO; GO:0043200; P:response to amino acid stimulus; IEA:Ensembl.
DR GO; GO:0048678; P:response to axon injury; IEA:Ensembl.
DR GO; GO:0046686; P:response to cadmium ion; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0009635; P:response to herbicide; IEA:Ensembl.
DR GO; GO:0010042; P:response to manganese ion; IEA:Ensembl.
DR GO; GO:0051597; P:response to methylmercury; IEA:Ensembl.
DR GO; GO:0010269; P:response to selenium ion; IEA:Ensembl.
DR GO; GO:0033189; P:response to vitamin A; IEA:Ensembl.
DR GO; GO:0033197; P:response to vitamin E; IEA:Ensembl.
DR GO; GO:0010043; P:response to zinc ion; IEA:Ensembl.
DR GO; GO:0000050; P:urea cycle; TAS:Reactome.
DR Gene3D; 3.40.800.10; -; 1.
DR InterPro; IPR014033; Arginase.
DR InterPro; IPR006035; Ureohydrolase.
DR InterPro; IPR023696; Ureohydrolase_domain.
DR InterPro; IPR020855; Ureohydrolase_Mn_BS.
DR PANTHER; PTHR11358; PTHR11358; 1.
DR Pfam; PF00491; Arginase; 1.
DR PIRSF; PIRSF036979; Arginase; 1.
DR PRINTS; PR00116; ARGINASE.
DR TIGRFAMs; TIGR01229; rocF_arginase; 1.
DR PROSITE; PS01053; ARGINASE_1; 1.
DR PROSITE; PS51409; ARGINASE_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Arginine metabolism;
KW Complete proteome; Cytoplasm; Disease mutation; Hydrolase; Manganese;
KW Metal-binding; Phosphoprotein; Polymorphism; Reference proteome;
KW Urea cycle.
FT CHAIN 1 322 Arginase-1.
FT /FTId=PRO_0000173693.
FT REGION 126 130 Substrate binding.
FT REGION 137 139 Substrate binding.
FT METAL 101 101 Manganese 1.
FT METAL 124 124 Manganese 1.
FT METAL 124 124 Manganese 2.
FT METAL 126 126 Manganese 2.
FT METAL 128 128 Manganese 1.
FT METAL 232 232 Manganese 1.
FT METAL 232 232 Manganese 2.
FT METAL 234 234 Manganese 2.
FT BINDING 183 183 Substrate.
FT MOD_RES 72 72 Phosphoserine (By similarity).
FT VAR_SEQ 43 43 Q -> QVTQNFLIL (in isoform 2).
FT /FTId=VSP_009330.
FT VAR_SEQ 204 289 Missing (in isoform 3).
FT /FTId=VSP_009331.
FT VARIANT 11 11 I -> T (in ARGIN; 12% of wild-type
FT activity; dbSNP:rs28941474).
FT /FTId=VAR_015594.
FT VARIANT 138 138 G -> V (in ARGIN).
FT /FTId=VAR_015595.
FT VARIANT 235 235 G -> R (in ARGIN).
FT /FTId=VAR_000674.
FT VARIANT 290 290 T -> S.
FT /FTId=VAR_000675.
FT CONFLICT 48 48 K -> E (in Ref. 3; AAL71547).
FT CONFLICT 86 86 E -> Q (in Ref. 1; AAA51776).
FT CONFLICT 202 202 E -> K (in Ref. 3; AAL71547).
FT STRAND 7 13
FT HELIX 22 26
FT HELIX 27 33
FT HELIX 36 42
FT STRAND 46 52
FT STRAND 67 69
FT HELIX 70 89
FT STRAND 93 99
FT HELIX 101 103
FT HELIX 104 114
FT STRAND 119 126
FT TURN 132 134
FT HELIX 140 142
FT HELIX 144 148
FT HELIX 150 152
FT TURN 153 155
FT HELIX 171 173
FT STRAND 174 179
FT HELIX 184 193
FT STRAND 196 199
FT HELIX 200 206
FT HELIX 208 220
FT STRAND 221 223
FT STRAND 227 232
FT HELIX 233 235
FT TURN 238 240
FT STRAND 243 246
FT HELIX 254 267
FT STRAND 270 276
FT HELIX 280 282
FT HELIX 286 303
SQ SEQUENCE 322 AA; 34735 MW; 8F3BE2652243F622 CRC64;
MSAKSRTIGI IGAPFSKGQP RGGVEEGPTV LRKAGLLEKL KEQECDVKDY GDLPFADIPN
DSPFQIVKNP RSVGKASEQL AGKVAEVKKN GRISLVLGGD HSLAIGSISG HARVHPDLGV
IWVDAHTDIN TPLTTTSGNL HGQPVSFLLK ELKGKIPDVP GFSWVTPCIS AKDIVYIGLR
DVDPGEHYIL KTLGIKYFSM TEVDRLGIGK VMEETLSYLL GRKKRPIHLS FDVDGLDPSF
TPATGTPVVG GLTYREGLYI TEEIYKTGLL SGLDIMEVNP SLGKTPEEVT RTVNTAVAIT
LACFGLAREG NHKPIDYLNP PK
//

MIM 207800
*RECORD*
*FIELD* NO
207800
*FIELD* TI
#207800 ARGININEMIA
;;ARGINASE DEFICIENCY;;
HYPERARGININEMIA;;
ARG1 DEFICIENCY
*FIELD* TX
read moreA number sign (#) is used with this entry because argininemia is caused
by mutation in the gene encoding liver arginase (ARG1; 608313).

DESCRIPTION

Arginase deficiency is an autosomal recessive inborn error of metabolism
caused by a defect in the final step in the urea cycle, the hydrolysis
of arginine to urea and ornithine.

Urea cycle disorders are characterized by the triad of hyperammonemia,
encephalopathy, and respiratory alkalosis. Five disorders involving
different defects in the biosynthesis of the enzymes of the urea cycle
have been described: ornithine transcarbamylase deficiency (311250),
carbamyl phosphate synthetase deficiency (237300), argininosuccinate
synthetase deficiency, or citrullinemia (215700), argininosuccinate
lyase deficiency (207900), and arginase deficiency.

CLINICAL FEATURES

Terheggen et al. (1969, 1970) described 2 sisters, aged 18 months and 5
years, with spastic paraplegia, epileptic seizures, and severe mental
retardation. The parents were related. Arginine levels were high in the
blood and spinal fluid of the patients, with intermediate elevations in
both parents and in 2 healthy sibs. Arginase activity in red cells was
very low in the patients and intermediate in the parents. In 1971
another affected girl was born into the family observed by Terheggen et
al. (1972, 1975). There was late introduction of a low protein diet, but
the infant developed severe mental retardation, athetosis, and
spasticity.

Cederbaum et al. (1977) reported a 7.5-year-old boy with progressive
psychomotor retardation, behavior disturbance, and spasticity, who had
growth arrest from age 3 years. Plasma arginine was increased, and red
blood cell arginase activity was less than 1% of normal, whereas it was
half-normal in both parents, 2 unaffected sibs, and in his paternal
grandfather. Cederbaum et al. (1977) concluded that arginase deficiency
is an autosomal recessive disorder. Michels and Beaudet (1978) reported
an affected Mexican child with growth retardation, microcephaly, mental
retardation, spasticity, and epileptiform discharges on EEG.

In the province of Quebec, Qureshi et al. (1983) identified an affected
French-Canadian family. Both parents showed activity of arginase 32 to
38% of normal. Walser (1983) stated that only 8 kindreds (with 13
patients) had been reported and that 4 of these (with 7 patients) were
Spanish or Spanish-American. Jorda et al. (1986) described an unusually
severe case of arginase deficiency in a Spanish infant who showed marked
protein intolerance early in life. The levels of red cell arginase in
the parents and 1 sister were consistent with heterozygosity. Brockstedt
et al. (1990) described argininemia in a 4-year-old boy born of
consanguineous Pakistani parents. He had microcephaly and spastic
tetraplegia. Pregnancy and birth were uneventful and psychomotor
development during the first 2 years of life were presumably normal.
Vilarinho et al. (1990) described argininemia in a 5-year-old Portuguese
boy who did not show spastic diplegia. His first manifestation, at 3.5
years of age, was a partial seizure for 15 minutes without loss of
consciousness. Six months later he showed the same clinical features
over a period of 15 days. The electroencephalogram showed partial left
temporal and paracentral spikes. At 4.5 years of age he began to have
episodes of vomiting, hypotonia, irritability, and ataxia.

In a patient dying with severe argininemia, Grody et al. (1989)
demonstrated total absence of arginase I in tissues, whereas arginase II
was increased about 4-fold in kidney. The patient, an offspring of
first-cousin parents of Cambodian descent, died at 6 months of age.
Although Southern blot analysis failed to show a substantial deletion in
the ARG1 gene, no cross-reactive arginine I protein could be
demonstrated by immunoprecipitation-competition and Western blot
analysis. Induction studies in cell lines that express only the type II
isozyme indicated that its activity could be enhanced several fold by
exposure to elevated arginine levels. This presumably was the mechanism
for the high level of the enzyme in the patient and explained the fact
that there is persistent ureagenesis in this disorder.

Christmann et al. (1990) described a patient in whom the diagnosis of
argininemia was first made at the age of 18 years when treatment with
sodium valproate was initiated for seizures. The patient had psychomotor
regression since the age of 15 months with paraparesis since she was 3
years old. By the age of 18, she was bedridden. Five days after the
initiation of valproate therapy, she went into a state of stupor and was
found to have marked hyperammonemia. 'Valproate sensitivity' has been
observed also with ornithine transcarbamylase deficiency and
citrullinemia, 2 other causes of hyperammonemia. Scheuerle et al. (1993)
described 2 unrelated patients, aged 9 and 5 years, who had been thought
to have cerebral palsy and were later found to have arginase deficiency.
The experience suggested that the condition may be underdiagnosed
because of its relatively mild symptoms. The authors noted that arginase
deficiency does not commonly have the severe hyperammonemia seen with
other urea cycle disorders.

Cowley et al. (1998) described an 18-year-old woman, born of related
parents, who had been well as a child with normal growth and
development. She presented for investigation of collapse with sudden
onset of spastic diplegia. She had mild, tender hepatomegaly. Over the
previous 6 months, she had been ill with episodic nausea and vomiting,
and had experienced some degree of lower limb weakness over the previous
2 weeks. The spastic diplegia in this patient was considered
stereotypical of arginase deficiency. No arginase activity was detected
in liver tissue; red cell arginase activity was low normal.

Picker et al. (2003) described a rare neonatal and fatal presentation of
arginase deficiency in a 2-day-old female with markedly elevated plasma
arginine, lactate, and CSF glutamine, and modestly elevated blood
ammonia, who developed hypertonia and tachypnea followed by intractable
seizures and global cerebral edema. The infant also had an atypical
presence of the ARG2 isozyme (107830) in the liver. Picker et al. (2003)
suggested that the cerebral edema and the fatal course, both of which
have been reported in older patients, were due to the increased
intracellular osmolarity of the elevated glutamine.

CLINICAL MANAGEMENT

Qureshi et al. (1984) recommended a combination of benzoate with
arginine restriction in the management of hyperargininemia. Bernar et
al. (1986) reported the case of a 12-year-old boy with less marked
elevations of plasma arginine and less severe intellectual impairment.
Both were attributed to a self-selected low-protein diet. Therapy with
sodium benzoate and dietary restriction caused an impressive
improvement.

MOLECULAR GENETICS

In a study of 20 persons homozygous or heterozygous for arginase
deficiency, Grody et al. (1989) found no substantial structural ARG1
gene deletions or other rearrangements by Southern blot analysis.

In a Japanese girl with argininemia, Haraguchi et al. (1990) found
compound heterozygosity for 2 frameshift deletions in the ARG1 gene
(608313.0001-608313.0002).

In 11 patients with argininemia, 9 separate mutations representing 21 of
the 22 mutant alleles were identified by Uchino et al. (1995) (see,
e.g., 608313.0008-608313.0011). Four of these mutations, accounting for
64% of the mutant alleles, were expressed in vitro and were found to be
severe or moderate. Patients with at least one 'moderate' mutant allele
responded well to dietary treatment, whereas patients with 2 'severe'
alleles did not respond to dietary treatment.

ANIMAL MODEL

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.

Iyer et al. (2002) produced Arg1-knockout mice that duplicated several
pathobiologic aspects of human argininemia.

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 found that the guanidino compounds
alpha-keto-delta-guanidinovaleric acid, alpha-N-acetylarginine, and
argininic acid were increased in brain tissue from the Arg1-deficient
mouse model of hyperargininemia. 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.

POPULATION GENETICS

The prevalence of argininemia is estimated to be 1 in 1,100,000 (Testai
and Gorelick, 2010).

HISTORY

The observation that researchers working with the Shope virus have low
blood arginine led to the use of Shope virus in the treatment of this
disorder. Rogers et al. (1973) reported an induction of arginase
activity by inoculation of the Shope virus into tissue cultures of an
argininemic patient's fibroblasts.

*FIELD* SA
Snyderman et al. (1977); Snyderman et al. (1979); Spector et al. (1980);
Spector et al. (1983); Uchino et al. (1992); Van Elsen and Leroy (1977)
*FIELD* RF
1. Bernar, J.; Hanson, R. A.; Kern, R.; Phoenix, B.; Shaw, K. N. F.;
Cederbaum, S. D.: Arginase deficiency in a 12-year-old boy with mild
impairment of intellectual function. J. Pediat. 108: 432-435, 1986.

2. Brockstedt, M.; Smit, L. M. E.; de Grauw, A. J. C.; van der Klei-van
Moorsel, J. M.; Jakobs, C.: A new case of hyperargininaemia: neurological
and biochemical findings prior to and during dietary treatment. Europ.
J. Pediat. 149: 341-343, 1990.

3. Cederbaum, S. D.; Shaw, K. N. F.; Valente, M.: Hyperargininemia. J.
Pediat. 90: 569-573, 1977.

4. Christmann, D.; Hirsch, E.; Mutschler, V.; Collard, M.; Marescaux,
C.; Colombo, J. P.: Argininemie congenitale diagnostiquee tardivement
a l'occasion de la prescription de valproate de sodium. Rev. Neurol. 146:
764-766, 1990.

5. Cowley, D. M.; Bowling, F. G.; McGill, J. J.; van Dongen, J.; Morris,
D.: Adult-onset arginase deficiency. J. Inherit. Metab. Dis. 21:
677-678, 1998.

6. Deignan, J. L.; Marescau, B.; Livesay, J. C.; Iyer, R. K.; De Deyn,
P. P.; Cederbaum, S. D.; Grody, W. W.: Increased plasma and tissue
guanidino compounds in a mouse model of hyperargininemia. Molec.
Genet. Metab. 93: 172-178, 2008.

7. Grody, W. W.; Argyle, C.; Kern, R. M.; Dizikes, G. J.; Spector,
E. B.; Strickland, A. D.; Klein, D.; Cederbaum, S. D.: Differential
expression of the two human arginase genes in hyperargininemia: enzymatic,
pathologic, and molecular analysis. J. Clin. Invest. 83: 602-609,
1989.

8. Haraguchi, Y.; Aparicio R., J. M.; Takiguchi, M.; Akaboshi, I.;
Yoshino, M.; Mori, M.; Matsuda, I.: Molecular basis of argininemia:
identification of two discrete frame-shift deletions in the liver-type
arginase gene. J. Clin. Invest. 86: 347-350, 1990.

9. Iyer, R. K.; Yoo, P. K.; Kern, R. M.; Rozengurt, N.; Tsoa, R.;
O'Brien, W. E.; Yu, H.; Grody, W. W.; Cederbaum, S. D.: Mouse model
for human arginase deficiency. Molec. Cell. Biol. 22: 4491-4498,
2002.

10. Jorda, A.; Rubio, V.; Portoles, M.; Vilas, J.; Garcia-Pino, J.
: A new case of arginase deficiency in a Spanish male. J. Inherit.
Metab. Dis. 9: 393-397, 1986.

11. Michels, V. V.; Beaudet, A. L.: Arginase deficiency in multiple
tissues in argininemia. Clin. Genet. 13: 61-67, 1978.

12. Picker, J. D.; Puga, A. C.; Levy, H. L.; Marsden, D.; Shih, V.
E.; DeGirolami, U.; Ligon, K. L.; Cederbaum, S. D.; Kern, R. M.; Cox,
G. F.: Arginase deficiency with lethal neonatal expression: evidence
for the glutamine hypothesis of cerebral edema. J. Pediat. 142:
349-352, 2003.

13. Qureshi, I. A.; Letarte, J.; Ouellet, R.; Batshaw, M. L.; Brusilow,
S.: Treatment of hyperargininemia with sodium benzoate and arginine-restricted
diet. J. Pediat. 104: 473-476, 1984.

14. Qureshi, I. A.; Letarte, J.; Ouellet, R.; Larochelle, J.; Lemieux,
B.: A new French-Canadian family affected by hyperargininaemia. J.
Inherit. Metab. Dis. 6: 179-182, 1983.

15. Rogers, S.; Lowenthal, A.; Terheggen, H. G.; Columbo, J. P.:
Induction of arginase activity with the Shope papilloma virus in tissue
culture cells from an argininemic patient. J. Exp. Med. 137: 1091-1096,
1973.

16. Scheuerle, A. E.; McVie, R.; Beaudet, A. L.; Shapira, S. K.:
Arginase deficiency presenting as cerebral palsy. Pediatrics 91:
995-996, 1993.

17. Shih, V. E.; Jones, C. T.; Levy, H. L.; Madigan, P. M.: Arginase
deficiency in Macaca fascicularis. I. Arginase activity and arginine
concentration in erythrocytes and liver. Pediat. Res. 6: 548-551,
1972.

18. Snyderman, S. E.; Sansaricq, C.; Chen, W. S.; Norton, P. M.; Phansalkar,
S. V.: Argininemia. J. Pediat. 90: 563-568, 1977.

19. Snyderman, S. E.; Sansaricq, C.; Norton, P. M.; Goldstein, F.
: Argininemia treated from birth. J. Pediat. 92: 61-63, 1979.

20. Spector, E. B.; Kiernan, M. B.; Cederbaum, S. D.: Properties
of fetal and adult red blood cell arginase: a possible diagnostic
test for arginase deficiency. Am. J. Hum. Genet. 32: 79-87, 1980.

21. Spector, E. B.; Rice, S. C. H.; Cederbaum, S. D.: Immunologic
studies of arginase in tissues of normal human adult and arginase-deficient
patients. Pediat. Res. 17: 941-944, 1983.

22. Terheggen, H. G.; Lavinha, F.; Colombo, J. P.; Van Sande, M.;
Lowenthal, A.: Familial hyperargininemia. J. Genet. Hum. 20: 69-84,
1972.

23. Terheggen, H. G.; Lowenthal, A.; Lavinha, F.; Colombo, J. P.:
Familial hyperargininaemia. Arch. Dis. Child. 50: 57-62, 1975.

24. Terheggen, H. G.; Schwenk, A.; Lowenthal, A.; Van Sande, M.; Colombo,
J. P.: Argininaemia with arginase deficiency. (Letter) Lancet 294:
748-749, 1969. Note: Originally Volume II.

25. Terheggen, H. G.; Schwenk, A.; Lowenthal, A.; Van Sande, M.; Colombo,
J. P.: Hyperargininaemie mit Arginasedefekt. Eine Neue familiaere
Stoffwechselstoerung. I. Klinische Befunde. Z. Kinderheilk. 107:
298-312, 1970.

26. Testai, F. D.; Gorelick, P. B.: Inherited metabolic disorders
and stroke part 2: homocystinuria, organic acidurias, and urea cycle
disorders. Arch. Neurol. 67: 148-153, 2010.

27. Uchino, T.; Haraguchi, Y.; Aparicio, J. M.; Mizutani, N.; Higashikawa,
M.; Naitoh, H.; Mori, M.; Matsuda, I.: Three novel mutations in the
liver-type arginase gene in three unrelated Japanese patients with
argininemia. Am. J. Hum. Genet. 51: 1406-1412, 1992.

28. Uchino, T.; Snyderman, S. E.; Lambert, M.; Qureshi, I. A.; Shapira,
S. K.; Sansaricq, C.; Smit, L. M. E.; Jakobs, C.; Matsuda, I.: Molecular
basis of phenotypic variation in patients with argininemia. Hum.
Genet. 96: 255-260, 1995.

29. Van Elsen, A. F.; Leroy, J. G.: Human hyperargininemia: a mutation
not expressed in skin fibroblasts? Am. J. Hum. Genet. 29: 350-355,
1977.

30. Vilarinho, L.; Senra, V.; Vilarinho, A.; Barbosa, C.; Parvy, P.;
Rabier, D.; Kamoun, P.: A new case of argininaemia without spastic
diplegia in a Portuguese male. J. Inherit. Metab. Dis. 13: 751-752,
1990.

31. Walser, M.: Urea cycle disorders and other hereditary hyperammonemic
syndromes.In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D.
S.; Goldstein, J. L.; Brown, M. S.: The Metabolic Basis of Inherited
Disease. New York: McGraw-Hill (pub.) (5th ed.): 1983. Pp. 402-438.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Growth failure

ABDOMEN:
[External features];
Anorexia;
Vomiting

NEUROLOGIC:
[Central nervous system];
Progressive spastic quadriplegia;
Seizures;
Developmental delay;
Mental retardation;
[Behavioral/psychiatric manifestations];
Hyperactivity;
Irritability

METABOLIC FEATURES:
Protein intolerance

LABORATORY ABNORMALITIES:
Hyperammonemia;
Hyperarginemia;
Diaminoaciduria (arginuria, lysinuria, cystinuria, ornithinuria);
Orotic aciduria;
Pyrimidinuria;
Elevated CSF amino acids (arginine, ornithine, aspartate, threonine,
glycine, and methionine)

MISCELLANEOUS:
Prevalence is estimated to be 1 in 1,100,000

MOLECULAR BASIS:
Caused by mutation in the arginase gene (ARG1, 207800.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2010
Kelly A. Przylepa - revised: 5/18/2001

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 07/17/2012
ckniffin: 10/11/2010
joanna: 8/23/2001
kayiaros: 5/18/2001

*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2010
Patricia A. Hartz - updated: 8/5/2005
Natalie E. Krasikov - updated: 2/10/2004
Cassandra L. Kniffin - reorganized: 12/4/2003
Carol A. Bocchini - updated: 12/14/1999
Victor A. McKusick - updated: 10/13/1998
Jennifer P. Macke - updated: 7/14/1997

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
terry: 04/21/2011
wwang: 10/29/2010
ckniffin: 10/11/2010
terry: 2/11/2009
mgross: 1/7/2009
mgross: 8/8/2005
terry: 8/5/2005
carol: 2/10/2004
carol: 12/4/2003
ckniffin: 12/3/2003
mcapotos: 12/14/1999
carol: 12/14/1999
terry: 6/11/1999
carol: 10/19/1998
terry: 10/13/1998
carol: 9/3/1998
jenny: 9/2/1997
mark: 9/1/1997
jenny: 8/13/1997
mimadm: 11/12/1995
mark: 10/2/1995
davew: 7/26/1994
carol: 4/11/1994
warfield: 3/23/1994
carol: 11/15/1993

MIM 608313
*RECORD*
*FIELD* NO
608313
*FIELD* TI
*608313 ARGINASE, LIVER; ARG1
*FIELD* TX

DESCRIPTION

Arginase (EC 3.5.3.1) catalyzes the last step of the urea cycle. It is
read morepresent 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.

CLONING

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.

GENE FUNCTION

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.

GENE STRUCTURE

Takiguchi et al. (1988) determined that the arginase gene contains 8
exons.

MAPPING

Sparkes et al. (1986) mapped the human liver arginase gene to 6q23
through a combination of somatic cell hybrid analysis and in situ
hybridization.

MOLECULAR GENETICS

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.

ANIMAL MODEL

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.

*FIELD* AV
.0001
ARGININEMIA
ARG1, 4-BP DEL

In a markedly retarded Japanese girl with 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 in exon 3, creating a stop codon at residue 132, and the other
was a 1-base deletion 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.

.0002
ARGININEMIA
ARG1, 1-BP DEL

See Haraguchi et al. (1990) and 608313.0001.

.0003
ARGININEMIA
ARG1, ARG291TER

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.

.0004
ARGININEMIA
ARG1, THR290SER

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.

.0005
ARGININEMIA
ARG1, TRP122TER

In a Japanese patient with argininemia (207800) manifested by
psychomotor retardation and spastic tetraplegia, Uchino et al. (1992)
identified a 365G-A nonsense mutation in the ARG1 gene (trp122-to-ter;
W122X). The patient was a compound heterozygote, having received this
mutation from his mother and a gly235-to-arg mutation (608313.0006) from
his father.

.0006
ARGININEMIA
ARG1, GLY235ARG

In 2 Japanese patients with argininemia (207800), Uchino et al. (1992)
identified a 703G-C mutation in exon 7 of the ARG1 gene, resulting in a
gly235-to-arg (G235R) substitution. One patient was a compound
heterozygote for this and the trp122-to-ter mutation (608313.0005); the
other patient was homozygous for the mutation.

.0007
ARGININEMIA
ARG1, 1-BP DEL, 842C

In a Japanese patient with argininemia (207800), Uchino et al. (1992)
identified a homozygous 1-bp deletion (842C) in exon 8 of the ARG1 gene,
resulting in a stop codon at residue 289.

.0008
ARGININEMIA
ARG1, ILE11THR

In 3 related Puerto Ricans 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 heterozygotes 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.

.0009
ARGININEMIA
ARG1, GLY138VAL

In a French-Canadian patient with argininemia (207800), Uchino et al.
(1995) identified a 413G-T change in exon 4 of the ARG1 gene, resulting
in a gly138-to-val (G138V) substitution. The other mutation in the
compound heterozygous patient was a donor site mutation (608313.0010).

.0010
ARGININEMIA
ARG1, IVS1, G-A, +1

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).

.0011
ARGININEMIA
ARG1, IVS4, A-G, -2

In a Pakistani patient with argininemia (207800) born of consanguineous
parents, Uchino et al. (1995) identified an A-G substitution at the
acceptor site of intron 4 of the ARG1 gene. The patient improved with
dietary therapy.

.0012
ARGININEMIA
ARG1, ARG21TER

In 4 unrelated Portuguese patients with argininemia (207800), Cardoso et
al. (1999) identified a C-T mutation in exon 2 of the ARG1 gene,
resulting in an arg21-to-ter (R21X) substitution.

*FIELD* SA
Grody et al. (1989); Grody et al. (1989)
*FIELD* RF
1. Cardoso, M. L.; Martins, E.; Vasconcelos, R.; Vilarinho, L.; Rocha,
J.: Identification of a novel R21X mutation in the liver-type arginase
gene (ARG1) in four Portuguese patients with argininemia. Hum. Mutat. 14:
355-356, 1999.

2. Deignan, J. L.; Livesay, J. C.; Yoo, P. K.; Goodman, S. I.; O'Brien,
W. E.; Iyer, R. K.; Cederbaum, S. D.; Grody, W. W.: Ornithine deficiency
in the arginase double knockout mouse. Molec. Genet. Metab. 89:
87-96, 2006.

3. Deignan, J. L.; Marescau, B.; Livesay, J. C.; Iyer, R. K.; De Deyn,
P. P.; Cederbaum, S. D.; Grody, W. W.: Increased plasma and tissue
guanidino compounds in a mouse model of hyperargininemia. Molec.
Genet. Metab. 93: 172-178, 2008.

4. Grody, W. W.; Argyle, C.; Kern, R. M.; Dizikes, G. J.; Spector,
E. B.; Strickland, A. D.; Klein, D.; Cederbaum, S. D.: Differential
expression of the two human arginase genes in hyperargininemia: enzymatic,
pathologic, and molecular analysis. J. Clin. Invest. 83: 602-609,
1989.

5. Grody, W. W.; Dodson, A.; Klein, D.; Kern, R. M.; Bassand, P.;
Cederbaum, S. D.: Molecular genetic study of human arginase deficiency.
(Abstract) Am. J. Hum. Genet. 45 (suppl.): A191 only, 1989.

6. Grody, W. W.; Klein, D.; Dodson, A. E.; Kern, R. M.; Wissmann,
P. B.; Goodman, B. K.; Bassand, P.; Marescau, B.; Kang, S.-S.; Leonard,
J. V.; Cederbaum, S. D.: Molecular genetic study of human arginase
deficiency. Am. J. Hum. Genet. 50: 1281-1290, 1992.

7. Haraguchi, Y.; Aparicio R., J. M.; Takiguchi, M.; Akaboshi, I.;
Yoshino, M.; Mori, M.; Matsuda, I.: Molecular basis of argininemia:
identification of two discrete frame-shift deletions in the liver-type
arginase gene. J. Clin. Invest. 86: 347-350, 1990.

8. Haraguchi, Y.; Takiguchi, M.; Amaya, Y.; Kawamoto, S.; Matsuda,
I.; Mori, M.: Molecular cloning and nucleotide sequence of cDNA for
human liver arginase. Proc. Nat. Acad. Sci. 84: 412-415, 1987.

9. Iyer, R. K.; Yoo, P. K.; Kern, R. M.; Rozengurt, N.; Tsoa, R.;
O'Brien, W. E.; Yu, H.; Grody, W. W.; Cederbaum, S. D.: Mouse model
for human arginase deficiency. Molec. Cell. Biol. 22: 4491-4498,
2002.

10. Shapiro, M. B.; Senapathy, P.: RNA splice junctions of different
classes of eukaryotes: sequence statistics and functional implications
in gene expression. Nucleic Acids Res. 15: 7155-7174, 1987.

11. Shih, V. E.; Jones, C. T.; Levy, H. L.; Madigan, P. M.: Arginase
deficiency in Macaca fascicularis. I. Arginase activity and arginine
concentration in erythrocytes and liver. Pediat. Res. 6: 548-551,
1972.

12. Snyderman, S. E.; Sansaricq, C.; Norton, P. M.; Goldstein, F.
: Argininemia treated from birth. J. Pediat. 92: 61-63, 1979.

13. Sparkes, R. S.; Dizikes, G. J.; Klisak, I.; Grody, W. W.; Mohandas,
T.; Heinzmann, C.; Zollman, S.; Lusis, A. J.; Cederbaum, S. D.: The
gene for human liver arginase (ARG1) is assigned to chromosome band
6q23. Am. J. Hum. Genet. 39: 186-193, 1986.

14. Spector, E. B.; Rice, S. C. H.; Cederbaum, S. D.: Immunologic
studies of arginase in tissues of normal human adult and arginase-deficient
patients. Pediat. Res. 17: 941-944, 1983.

15. Spector, E. B.; Rice, S. C. H.; Kern, R. M.; Hendrickson, R.;
Cederbaum, S. D.: Comparison of arginase activity in red blood cells
of lower mammals, primates, and man: evolution to high activity in
primates. Am. J. Hum. Genet. 37: 1138-1145, 1985.

16. Stoermer, K. A.; Burrack, A.; Oko, L.; Montgomery, S. A.; Borst,
L. B.; Gill, R. G.; Morrison, T. E.: Genetic ablation of arginase
1 in macrophages and neutrophils enhances clearance of an arthritogenic
alphavirus. J. Immun. 189: 4047-4059, 2012.

17. Takiguchi, M.; Haraguchi, Y.; Mori, M.: Human liver-type arginase
gene: structure of the gene and analysis of the promoter region. Nucleic
Acids Res. 16: 8789-8802, 1988.

18. Terasaki, K.; Spector, E. B.; Hendrickson, R.; Cederbaum, S. D.
: Properties of arginase from liver of Macaca fascicularis: comparison
of normals with red blood cell arginase deficient monkeys. Biochem.
Genet. 18: 829-841, 1980.

19. Uchino, T.; Haraguchi, Y.; Aparicio, J. M.; Mizutani, N.; Higashikawa,
M.; Naitoh, H.; Mori, M.; Matsuda, I.: Three novel mutations in the
liver-type arginase gene in three unrelated Japanese patients with
argininemia. Am. J. Hum. Genet. 51: 1406-1412, 1992.

20. Uchino, T.; Snyderman, S. E.; Lambert, M.; Qureshi, I. A.; Shapira,
S. K.; Sansaricq, C.; Smit, L. M. E.; Jakobs, C.; Matsuda, I.: Molecular
basis of phenotypic variation in patients with argininemia. Hum.
Genet. 96: 255-260, 1995.

*FIELD* CN
Paul J. Converse - updated: 06/19/2013
Patricia A. Hartz - updated: 1/6/2009
Patricia A. Hartz - updated: 8/8/2005

*FIELD* CD
Cassandra L. Kniffin: 12/3/2003

*FIELD* ED
mgross: 06/19/2013
alopez: 7/16/2012
joanna: 12/8/2011
mgross: 1/7/2009
terry: 1/6/2009
mgross: 8/8/2005
carol: 12/4/2003
ckniffin: 12/3/2003