Abstract
Arginase-1 (ARG1) deficiency is a rare autosomal recessive disorder that affects the liver-based urea cycle, leading to impaired ureagenesis. This genetic disorder is caused by 40+ mutations found fairly uniformly spread throughout the ARG1 gene, resulting in partial or complete loss of enzyme function, which catalyzes the hydrolysis of arginine to ornithine and urea. ARG1-deficient patients exhibit hyperargininemia with spastic paraparesis, progressive neurological and intellectual impairment, persistent growth retardation, and infrequent episodes of hyperammonemia, a clinical pattern that differs strikingly from other urea cycle disorders. This review briefly highlights the current understanding of the etiology and pathophysiology of ARG1 deficiency derived from clinical case reports and therapeutic strategies stretching over several decades and reports on several exciting new developments regarding the pathophysiology of the disorder using ARG1 global and inducible knockout mouse models. Gene transfer studies in these mice are revealing potential therapeutic options that can be exploited in the future. However, caution is advised in extrapolating results since the lethal disease phenotype in mice is much more severe than in humans indicating that the mouse models may not precisely recapitulate human disease etiology. Finally, some of the functions and implications of ARG1 in non-urea cycle activities are considered. Lingering questions and future areas to be addressed relating to the clinical manifestations of ARG1 deficiency in liver and brain are also presented. Hopefully, this review will spark invigorated research efforts that lead to treatments with better clinical outcomes.
Similar content being viewed by others
References
Jackson MJ, Beaudet AL, O’Brien WE (1986) Mammalian urea cycle enzymes. Annu Rev Genet 20:431–464
Kossel A, Dakin HD (1904) Über die Arginase. Z Physiol Chem 41:321–331
Iyer RK, Jenkinson CP, Vockley JG, Kern RM, Grody WW, Cederbaum SD (1998) The human arginases and arginase deficiency. J Inherit Metab Dis 21:86–100
Waddington SN, Mosley K, Cook HT, Tam FWK, Cattell V (1998) Arginase AI is upregulated in acute immune complex-induced inflammation. Biochem Biophys Res Commun 247:84–87
Zhang C, Hein TW, Wang W, Chang C-I, Kuo L (2001) Constitutive expression of arginase in microvascular endothelial cells counteracts nitric oxide-mediated vasodilatory function. FASEB J 15:1264–1266
Morris SM Jr, Bhamidipati D, Kepka-Lenhart D (1997) Human type ll arginase: sequence analysis and tissue-specific expression. Gene 193:157–161
Yip MCM, Knox WE (1972) Function of arginase in lactating mammary gland. Biochem J 127:893–899
Jenkinson CP, Grody WW, Cederbaum SD (1996) Comparative properties of arginases. Comp Biochem Physiol 114B:107–132
Vockley JG, Jenkinson CP, Shukla H, Kern RM, Grody WW, Cederbaum SD (1996) Cloning and characterization of the human type II arginase gene. Genomics 38:118–123
Li H, Meininge CJ, Hawker JR Jr, Haynes TE, Kepka-Lenhart D, Mistry SK, Morris SM Jr, Wu G (2001) Regulatory role of arginase I and II in nitric oxide, polyamine, and proline syntheses in endothelial cells. Am J Physiol Endocrinol Metab 280:E75–E82
Kanyo ZF, Scolnick LR, Ash DE, Christianson DW (1996) Structure of a unique binuclear manganese cluster in arginase. Nature 383:554–557
Reczkowski RS, Ash DE (1992) EPR evidence for binuclear manganese (II) centers in rat liver arginase. J Am Chem Soc 114:10992–10994
Carvajal N, Torres C, Uribe E, Salas M (1995) Interaction of arginase with metal ions: studies of the enzyme from human liver and comparison with other arginases. Comp Biochem Physiol B Biochem Mol Biol 112:153–159
Cama E, Emig FA, Ash DE, Christianson DW (2003) Structural and functional importance of first-shell metal ligands in the binuclear manganese cluster of arginase I. Biochemistry 42:7748–7758
Di Costanzo L, Pique ME, Christianson DQ (2007) Crystal structure of human arginase 1 complexed with thiosemicarbazide reveals an unusual thiocarbonyl μ-sulfide ligand in the binuclear manganese cluster. J Am Chem Soc 129:6388–6389
Terheggen HG, Lowenthal A, van Sande M, Colombo JP (1969) Argininaemia with arginase deficiency. Lancet 2:748–749
Cederbaum SD, Shaw KN, Valente M (1977) Hyperargininemia. J Pediatr 90:569–573
Cederbaum SD, Shaw KN, Spector EB, Verity MA, Snodgrass PJ, Sugarman GI (1979) Hyperargininemia with arginase deficiency. Pediatr Res 13:827–833
Grody WW, Kern RM, Klein D, Dodson AE, Wissman PB, Barsky SH, Cederbaum SD (1993) Arginase deficiency manifesting delayed clinical sequelae and induction of a kidney arginase isozyme. Hum Genet 91:1–5
Prasad AN, Breen JC, Ampola MG, Rosman NP (1997) Argininemia: a treatable genetic cause of progressive spastic diplegia simulating cerebral palsy: case reports and literature review. J Child Neurol 12:301–309
Scholl-Bürgi S, Sigl SB, Häberle J, Haberlandt E, Rostásy K, Ertl C, Eichinger-Öttl U, Heinz-Erian P, Karall D (2008) Amino acids in CSF and plasma in hyperammonaemic coma due to arginase1 deficiency. J Inherit Metab Dis 31(Suppl 2):S323–S328
Schiff M, Benoist JF, Cardoso ML, Elmaleh-Bergès M, Forey P, Santiago J, Ogier de Baulny H (2009) Early-onset hyperargininaemia: a severe disorder? J Inherit Metab Dis 32(Suppl 1):S175–S178
Jain-Ghai S, Nagamani SC, Blaser S, Siriwardena K, Feigenbaum A (2011) Arginase I deficiency: severe infantile presentation with hyperammonemia: more common than reported? Mol Genet Metab 104(1–2):107–111, Erratum in: (2012) Mol Genet Metab105:159
Grody WW, Chang RJ, Panagiotis NM, Matz D, Cederbaum SD (1994) Menstrual cycle and gonadal steroid effects on symptomatic hyperammonaemia of urea-cycle-based and idiopathic aetiologies. J Inherit Metab Dis 17:566–574
Boles RG, Stone ML (2006) A patient with arginase deficiency and episodic hyperammonemia successfully treated with menses cessation. Mol Genet Metab 89:390–391
De Deyn PP, Marescau B, Qureshi IA et al (1997) Hyperargininemia: a treatable inborn error of metabolism? In: De Deyn PP, Marescau B, Qureshi IA, Mori A (eds) Guanidino compounds in biology & medicine II. John Libbey & Company Ltd., London, pp 53–69
Gungor S, Akinci A, Firat AK, Tabel Y, Alkan A (2008) Neuroimaging findings in hyperargininemia. J Neuroimaging 18:457–462
Scaglia F, Lee B (2006) Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency. Am J Med Genet C: Semin Med Genet 142:113–120
Gallagher RC, Lam C, Wong D, Cederbaum S, Sokol RJ (2014) Significant hepatic involvement in patients with ornithine transcarbamylase deficiency. J Pediatr 164:720–725
Braga AC, Vilarinho L, Ferreira E, Rocha H (1997) Hyperargininemia presenting as persistent neonatal jaundice and hepatic cirrhosis. J Pediatr Gastroenterol Nutr 24:218–221
Gomes ME, Santos SE, Vilarinho S, Saudubray JM, Vilarinho L (2010) Neonatal cholestasis: an uncommon presentation of hyperargininemia. J Inherit Metab Dis 33(Suppl 3):S503–S506
Amayreh W, Meyer U, Das AM (2014) Treatment of arginase deficiency revisited: guanidinoacetate as a therapeutic target and biomarker for therapeutic monitoring. Dev Med Child Neurol 56:1021–1024
Lee BH, Jin HY, Kim GH, Choi JH, Yoo HW (2011) Argininemia presenting with progressive spastic diplegia. Pediatr Neurol 44:218–220
Uchino T, Snyderman SE, Lambert M, Qureshi IA, Shapira SK, Sansaricq C, Smit LM, Jakobs C, Matsuda I (1995) Molecular basis of phenotypic variation in patients with argininemia. Hum Genet 96:255–260
Uchino T, Haraguchi Y, Aparicio JM, Mizutani N, Higashikawa M, Naitoh H, Mori M, Matsuda I (1992) Three novel mutations in the liver-type arginase gene in three unrelated Japanese patients with argininemia. Am J Hum Genet 51:1406–1412
Carvalho DR, Brand GD, Brum JM, Takata RI, Speck-Martins CE, Pratesi R (2012) Analysis of novel ARG1 mutations causing hyperargininemia and correlation with arginase I activity in erythrocytes. Gene 509:124–130
Wu TF, Liu YP, Li XY, Wang Q, Ding Y, Ma YY, Song JQ, Yang YL (2013) Five novel mutations in ARG1 gene in Chinese patients of argininemia. Pediatr Neuro l49:119–123
Korman SH, Gutman A, Stemmer E, Kay BS, Ben-Neriah Z, Zeigler M (2004) Prenatal diagnosis for arginase deficiency by second-trimester fetal erythrocyte arginase assay and first-trimester ARG1 mutation analysis. Prenat Diagn 24:857–860
Cardoso ML, Martins E, Vasconcelos R, Vilarinho L, Rocha J (1999) Identification of a novel R21X mutation in the liver-type arginase gene (ARG1) in four Portuguese patients with argininemia. Hum Mutat 14:355–366
Segawa Y, Matsufuji M, Itokazu N, Utsunomiya H, Watanabe Y, Yoshino M, Takashima S (2011) A long-term survival case of arginase deficiency with severe multicystic white matter and compound mutations. Brain Dev 33:45–48
Haraguchi Y, Aparicio JM, Takiguchi M, AkaboshiI YM, Mori M, Matsuda I (1990) Molecular basis of argininemia. Identification of two discrete frame-shift deletions in the liver-type arginase gene. J Clin Invest 86:347–350
Hertecant JL, Al-Gazali LI, Karuvantevida NS, Ali BR (2009) A novel mutation in ARG1 gene is responsible for arginase deficiency in an Asian family. Saudi Med J 30:1601–1603
Edwards RL, Moseley K, Watanabe Y, Wong LJ, Ottina J, Yano S (2009) Long-term neurodevelopmental effects of early detection and treatment in a 6-year-old patient with argininaemia diagnosed by newborn screening. J Inherit Metab Dis 32(Suppl 1):S197–S200
Cohen YH, Bargal R, Zeigler M, Markus-Eidlitz T, Zuri V, Zeharia A (2012) Hyperargininemia: a family with a novel mutation in an unexpected site. JIMD Rep 5:83–88
Vockley JG, Tabor DE, Kern RM, Goodman BK, Wissmann PB, Kang DS, Grody WW, Cederbaum SD (1994) Identification of mutations (D128G, H141L) in the liver arginase gene of patients with hyperargininemia. Hum Mutat 4:150–154
Vockley JG, Goodman BK, Tabor DE, Kern RM, Jenkinson CP, Grody WW, Cederbaum SD (1996) Loss of function mutations in conserved regions of the human arginase I gene. Biochem Mol Med 59:44–51
Tsang JP, Poon WL, Luk HM, Fung CW, Ching CK, Mak CM, Lam CW, Siu TS, Tam S, Wong VC (2012) Arginase deficiency with new phenotype and a novel mutation: contemporary summary. Pediatr Neurol 47:263–269
Häberle J, Koch HG (2004) Genetic approach to prenatal diagnosis in urea cycle defects. Prenat Diagn 24:378–383
Wu T, Li X, Ding Y, Liu Y, Song J, Wang Q, Li M, Qin Y, Yang Y, Zhonghua (2015) Seven patients of argininemia with spastic tetraplegia as the first and major symptom and prenatal diagnosis of two fetuses with high risk. Er Ke Za Zhi 53:425–430
Summar ML, Koelker S, Freedenberg D, Le Mons C, Haberle J, Lee HS, Kirmse B, European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD); Members of the Urea Cycle Disorders Consortium (UCDC) (2013) The incidence of urea cycle disorders. Mol Genet Metab 110:179–180
Ash DE, Scolnick LR, Kanyo ZF, Vockley JG, Cederbaum SD, Christianson DW (1998) Molecular basis of hyperargininemia: structure function consequences of mutations in human liver arginase. Mol Genet Metab 64:243–249
Dizikes GJ, Spector EB, Cederbaum SD (1986) Cloning of rat liver arginase cDNA and elucidation of regulation of arginase gene expression in H4 rat hepatoma cells. Somat Cell Mol Genet 12:375–384
Takiguchi M, Haraguchi Y, Mori M (1988) Human liver-type arginase gene: structure of the gene and analysis of the promoter region. Nucleic Acids Res 16:8789–8802
Iyer RK, Yoo PK, Kern RM, Rozengurt N, Tsoa R, O’Brien WE, Yu H, Grody WW, Cederbaum SD (2002) Mouse model for human arginase deficiency. Mol Cell Biol 22:4491–4498
Deignan JL, Livesay JC, Yoo PK, Goodman SI, O’Brien WE, Iyer RK, Cederbaum SD, Grody WW (2006) Ornithine deficiency in the arginase double knockout mouse. Mol Genet Metab 89:87–96
Deignan JL, Marescau B, Livesay JC, Iyer RK, De Deyn PP, Cederbaum SD, Grody WW (2008) Increased plasma and tissue guanidino compounds in a mouse model of hyperargininemia. Mol Genet Metab 93:172–178
Sin YY, Ballantyne LL, Mukherjee K, St Amand T, Kyriakopoulou L, Schulze A, Funk CD (2013) Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism. PLoS One 8:e80001
Kasten J, Hu C, Bhargava R, Park H, Tai D, Byrne JA, Marescau B, De Deyn PP, Schlichting L, Grody WW et al (2013) Lethal phenotype in conditional late-onset arginase 1 deficiency in the mouse. Mol Genet Metab 110:222–230
Lee EK, Hu C, Bhargava R, Rozengurt N, Stout D, Grody WW, Cederbaum SD, Lipshutz GS (2012) Long-term survival of the juvenile lethal arginase-deficient mouse with AAV gene therapy. Mol Ther 20:1844–1851
Deignan JL, De Deyn PP, Cederbaum SD, Fuchshuber A, Roth B, Gsell W, Marescau B (2010) Guanidino compound levels in blood, cerebrospinal fluid, and post-mortem brain material of patients with argininemia. Mol Genet Metab 100(Suppl 1):S31–S36
Gau CL, Rosenblatt RA, Cerullo V, Lay FD, Dow AC, Livesay J, Brunetti-Pierri N, Lee B, Cederbaum SD, Grody WW et al (2009) Short-term correction of arginase deficiency in a neonatal murine model with a helper-dependent adenoviral vector. Mol Ther 17:1155–1163
Lee EK, Hu C, Bhargava R, Ponnusamy R, Park H, Novicoff S, Rozengurt N, Marescau B, De Deyn P, Stout D et al (2013) AAV-based gene therapy prevents neuropathology and results in normal cognitive development in the hyperargininemic mouse. Gene Ther 20:785–796
Huh WJ, Khurana SS, Geahlen JH, Kohli K, Waller RA, Mills JC (2012) Tamoxifen induces rapid, reversible atrophy, and metaplasia in mouse stomach. Gastroenterology 142:21–24
Mellinkoff SM, Frankland M, Boyle D, Greip M (1956) Relationship between serum amino acid concentration and fluctuations in appetite. J Appl Physiol 8:535–538
Feldman JM, Lebovitz HE (1971) Ammonium ion, a modulator of insulin secretion. Am J Physiol 221:1027–1032
Ballantyne LL, Sin YY, St Amand T, Si J, Goossens S, Haenebalcke L, Haigh JJ, Kyriakopoulou L, Schulze A, Funk CD (2015) Strategies to rescue the consequences of inducible arginase-1 deficiency in mice. PLoS One 10:e0125967
Michels VV, Beaudet AL (1978) Arginase deficiency in multiple tissues in argininemia. Clin Genet 13:61–67
Sakiyama T, Nakabayashi H, Shimizu H, Kondo W, Kodama S, Kitagawa T (1984) A successful trial of enzyme replacement therapy in a case of argininemia. Tohoku J Exp Med 142:239–248
Mizutani N, Hayakawa C, Maehara M, Watanabe K (1987) Enzyme replacement therapy in a patient with hyperargininemia. Tohoku J Exp Med 151:301–307
Burrage LC, Sun Q, Elsea SH, Jiang MM, Nagamani SC, Frankel AE, Stone E, Alters SE, Johnson DE, Rowlinson SW et al. (2015) Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency. Hum Mol Genet. doi: 10.1093/hmg/ddv352.
Whitington PF, Alonso EM, Boyle JT, Molleston JP, Rosenthal P, Emond JC, Millie JM (1998) Liver transplantation for the treatment of urea cycle disorders. J Inherit Metab Dis 21(Suppl 1):112–118
Mace H, Srinivas C, Selzner M, Minkovich L (2014) Anesthetic management of a patient with arginase deficiency undergoing liver transplantation. A A Case Rep 3:85–87
Terheggen HG, Lowenthal A, Lavinha F, Colombo JP, Rogers S (1975) Unsuccessful trial of gene replacement in arginase deficiency. Z Kinderheilkd 119:1–3
Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Crespo PS, Santer R et al (2012) Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 7:32
Terheggen HG, Lavinha F, Colombo JP, Van SM, Lowenthal A (1972) Familial hyperargininemia. J Genet Hum 20:69–84
Cederbaum SD, Moedjono SJ, Shaw KN, Carter M, Naylor E, Walzer M (1982) Treatment of hyperargininaemia due to arginase deficiency with a chemically defined diet. J Inherit Metab Dis 5:95–99
Snyderman SE, Sansaricq C, Chen WJ, Norton PM, Phansalkar SV (1977) Argininemia. J Pediatr 90:563–568
Qureshi IA, Letarte J, Ouellet R, Lelievre M, Laberge C (1981) Ammonia metabolism in a family affected by hyperargininemia. Diabete Metab 7:5–11
Batshaw ML, MacArthur RB, Tuchman M (2001) Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr 138:S46–S54
Pardridge WM (1977) Lysine supplementation in hyperargininemia. J Pediatr 91:1032–1033
Kang SS, Wong PW, Melyn MA (1983) Hyperargininemia: effect of ornithine and lysine supplementation. J Pediatr 103:763–765
Wijnands KA, Hoeksema MA, Meesters DM, van den Akker NM, Molin DG, Briedé JJ, Ghosh M, Köhler SE, van Zandvoort MA, de Winther MP et al (2014) Arginase-1 deficiency regulates arginine concentrations and NOS2-mediated NO production during endotoxemia. PLoS One 9(1):e86135
Bode-Böger SM, Scalera F, Ignarro LJ (2007) The L-arginine paradox: importance of the L-arginine/asymmetrical dimethylarginine ratio. Pharmacol Ther 114:295–306
Caldwell RB, Toque HA, Narayanan SP, Caldwell RW (2015) Arginase: an old enzyme with new tricks. Trends Pharmacol Sci 36:395–405
Popovic PJ, Zeh HJ 3rd, Ochoa JB (2007) Arginine and immunity. J Nutr 137:1681S–1686S
Sharda DR, Yu S, Ray M, Squadrito ML, De Palma M, Wynn TA, Morris SM Jr, Hankey PA (2011) Regulation of macrophage arginase expression and tumor growth by the Ron receptor tyrosine kinase. J Immunol 187:2181–2192
Raber PL, Thevenot P, Sierra R, Wyczechowska D, Halle D, Ramirez ME, Ochoa AC, Fletcher M, Velasco C, Wilk A et al (2014) Subpopulations of myeloid-derived suppressor cells impair T cell responses through independent nitric oxide-related pathways. Int J Cancer 134:2853–2864
Raber P, Ochoa AC, Rodríguez PC (2012) Metabolism of L-arginine by myeloid-derived suppressor cells in cancer: mechanisms of T cell suppression and therapeutic perspectives. Immunol Invest 41:614–634
Maarsingh H, Zaagsma J, Meurs H (2009) Arginase: a key enzyme in the pathophysiology of allergic asthma opening novel therapeutic perspectives. Br J Pharmacol 158:652–664
North ML, Khanna N, Marsden PA, Grasemann H, Scott JA (2009) Functionally important role for arginase 1 in the airway hyperresponsiveness of asthma. Am J Physiol Lung Cell Mol Physiol 296:L911–L920
Mabalirajan U, Ahmad T, Leishangthem GD, Joseph DA, Dinda AK, Agrawal A, Ghosh B (2010) Beneficial effects of high dose of L-arginine on airway hyperresponsiveness and airway inflammation in a murine model of asthma. J Allergy Clin Immunol 125:626–635
Yang M, Rangasamy D, Matthaei KI, Frew AJ, Zimmmermann N, Mahalingam S, Webb DC, Tremethick DJ, Thompson PJ, Hogan SP et al (2006) Inhibition of arginase I activity by RNA interference attenuates IL-13-induced airways hyperresponsiveness. J Immunol 177:5595–5603
Deignan JL, Livesay JC, Shantz LM, Pegg AE, O’Brien WE, Iyer RK, Cederbaum SD, Grody WW (2007) Polyamine homeostasis in arginase knockout mice. Am J Physiol Cell Physiol 293:C1296–C1301
Kepka-Lenhart D, Mistry SK, Wu G, Morris SM Jr (2000) Arginase I: a limiting factor for nitric oxide and polyamine synthesis by activated macrophages? Am J Physiol Regul Integr Comp Physiol 279:R2237–R2242
Munder M, Mollinedo F, Calafat J, Canchado J, Gil-Lamaignere C, Fuentes JM, Luckner C, Doschko G, Soler G, Eichmann K et al (2005) Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity. Blood 105:2549–2556
Li M, Suzuki K, Kim NY, Liu GH, Izpisua Belmonte JC (2014) A cut above the rest: targeted genome editing technologies in human pluripotent stem cells. J Biol Chem 289:4594–4599
Cox DB, Platt RJ, Zhang F (2015) Therapeutic genome editing: prospects and challenges. Nat Med 21:121–131
Acknowledgments
CDF is a Tier 1 Canada Research Chair holder in Molecular, Cellular, and Physiological Medicine and kindly acknowledges the CRC program support.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Disclosures
A.S. is a paid consultant of Hyperion Therapeutics Inc. (Brisbane, CA, USA) and Medunik Canada (Blainville, QC, Canada). The other authors have no conflicts of interest to declare.
Rights and permissions
About this article
Cite this article
Sin, Y.Y., Baron, G., Schulze, A. et al. Arginase-1 deficiency. J Mol Med 93, 1287–1296 (2015). https://doi.org/10.1007/s00109-015-1354-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-015-1354-3