Mouse model for human arginase deficiency.
Deficiency of liver arginase (AI) causes hyperargininemia (OMIM 207800), a disorder characterized by progressive mental impairment, growth retardation, and spasticity and punctuated by sometimes fatal episodes of hyperammonemia. We constructed a knockout mouse strain carrying a nonfunctional AI gene by homologous recombination. Arginase AI knockout mice completely lacked liver arginase (AI) activity, exhibited severe symptoms of hyperammonemia, and died between postnatal days 10 and 14. During hyperammonemic crisis, plasma ammonia levels of these mice increased >10-fold compared to those for normal animals. Livers of AI-deficient animals showed hepatocyte abnormalities, including cell swelling and inclusions. Plasma amino acid analysis showed the mean arginine level in knockouts to be approximately fourfold greater than that for the wild type and threefold greater than that for heterozygotes; the mean proline level was approximately one-third and the ornithine level was one-half of the proline and ornithine levels, respectively, for wild-type or heterozygote mice--understandable biochemical consequences of arginase deficiency. Glutamic acid, citrulline, and histidine levels were about 1.5-fold higher than those seen in the phenotypically normal animals. Concentrations of the branched-chain amino acids valine, isoleucine, and leucine were 0.4 to 0.5 times the concentrations seen in phenotypically normal animals. In summary, the AI-deficient mouse duplicates several pathobiological aspects of the human condition and should prove to be a useful model for further study of the disease mechanism(s) and to explore treatment options, such as pharmaceutical administration of sodium phenylbutyrate and/or ornithine and development of gene therapy protocols.
Iyer
Ramaswamy K
RK
Department of Pathology and Laboratory Medicine and the Mental Retardation Research Center, University of California Los Angeles School of Medicine, Los Angeles, California 90095-1732, USA. riyer@mednet.ucla.edu
Yoo
Paul K
PK
Kern
Rita M
RM
Rozengurt
Nora
N
Tsoa
Rosemarie
R
O'Brien
William E
WE
Yu
Hong
H
Grody
Wayne W
WW
Cederbaum
Stephen D
SD
D000818:Animals; D000831:Animals, Newborn; D001119:Arginase / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D020162:Hyperargininemia / Q000235:genetics* / Q000503:physiopathology*; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000644:Quaternary Ammonium Compounds / Q000097:blood
D000644:Quaternary Ammonium Compounds; D001119:Arginase