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J Mol Med (Berl). 2015 Dec;93(12):1287-96. doi: 10.1007/s00109-015-1354-3. Epub 2015 Oct 14.

Arginase-1 deficiency.

Author information

1
Department of Biomedical and Molecular Sciences, Queen's University, 433 Botterell Hall, 18 Stuart Street, Kingston, ON, K7L 3N6, Canada.
2
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.
3
Genetics and Genome Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada.
4
Department of Biomedical and Molecular Sciences, Queen's University, 433 Botterell Hall, 18 Stuart Street, Kingston, ON, K7L 3N6, Canada. funkc@queensu.ca.

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.

KEYWORDS:

Arginine; Hepatocyte; Mouse models; Rare genetic disorder; Urea cycle

PMID:
26467175
DOI:
10.1007/s00109-015-1354-3
[Indexed for MEDLINE]

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