caa a22 4500 60554333X CHVBK 20210128100926.0 cr unu---uuuuu 210128e20151201xx s 000 0 eng 10.1007/s00109-015-1354-3 doi (NATIONALLICENCE)springer-10.1007/s00109-015-1354-3 Arginase-1 deficiency [Elektronische Daten] [Yuan Sin, Garrett Baron, Andreas Schulze, Colin Funk] 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. Springer-Verlag Berlin Heidelberg, 2015 Urea cycle nationallicence Arginine nationallicence Hepatocyte nationallicence Mouse models nationallicence Rare genetic disorder nationallicence Sin Yuan Department of Biomedical and Molecular Sciences, Queen's University, 433 Botterell Hall, 18 Stuart Street, K7L 3N6, Kingston, ON, Canada aut Baron Garrett Department of Biomedical and Molecular Sciences, Queen's University, 433 Botterell Hall, 18 Stuart Street, K7L 3N6, Kingston, ON, Canada aut Schulze Andreas Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada aut Funk Colin Department of Biomedical and Molecular Sciences, Queen's University, 433 Botterell Hall, 18 Stuart Street, K7L 3N6, Kingston, ON, Canada aut Journal of Molecular Medicine Springer Berlin Heidelberg 93/12(2015-12-01), 1287-1296 0946-2716 93:12<1287 2015 93 109 https://doi.org/10.1007/s00109-015-1354-3 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 review-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00109-015-1354-3 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sin Yuan Department of Biomedical and Molecular Sciences, Queen's University, 433 Botterell Hall, 18 Stuart Street, K7L 3N6, Kingston, ON, Canada aut NATIONALLICENCE 700 1- Baron Garrett Department of Biomedical and Molecular Sciences, Queen's University, 433 Botterell Hall, 18 Stuart Street, K7L 3N6, Kingston, ON, Canada aut NATIONALLICENCE 700 1- Schulze Andreas Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada aut NATIONALLICENCE 700 1- Funk Colin Department of Biomedical and Molecular Sciences, Queen's University, 433 Botterell Hall, 18 Stuart Street, K7L 3N6, Kingston, ON, Canada aut NATIONALLICENCE 773 0- Journal of Molecular Medicine Springer Berlin Heidelberg 93/12(2015-12-01), 1287-1296 0946-2716 93:12<1287 2015 93 109