Journal of Molecular Medicine

, Volume 93, Issue 12, pp 1287–1296 | Cite as

Arginase-1 deficiency

  • Yuan Yan Sin
  • Garrett Baron
  • Andreas Schulze
  • Colin D. FunkEmail author


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.


Urea cycle Arginine Hepatocyte Mouse models Rare genetic disorder 



CDF is a Tier 1 Canada Research Chair holder in Molecular, Cellular, and Physiological Medicine and kindly acknowledges the CRC program support.

Compliance with ethical standards


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.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Yuan Yan Sin
    • 1
  • Garrett Baron
    • 1
  • Andreas Schulze
    • 2
    • 3
  • Colin D. Funk
    • 1
    Email author
  1. 1.Department of Biomedical and Molecular SciencesQueen’s UniversityKingstonCanada
  2. 2.Division of Clinical and Metabolic GeneticsThe Hospital for Sick Children and University of TorontoTorontoCanada
  3. 3.Genetics and Genome Biology Program, Peter Gilgan Centre for Research and LearningThe Hospital for Sick ChildrenTorontoCanada

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