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Molecular and Cellular Biology, January 2004, p. 527-536, Vol. 24, No. 2
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.2.527-536.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Slc25a13-Knockout Mice Harbor Metabolic Deficits but Fail To Display Hallmarks of Adult-Onset Type II Citrullinemia

Genetics & Genomic Biology,¹ Metabolism Research Programs, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8,⁶ Department of Molecular & Medical Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8,² Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531,³ Department of Molecular Metabolism & Biochemical Genetics,⁴ Laboratory for Neuroanatomy, Kagoshima University Graduate School of Medical & Dental Sciences, Kagoshima 890-8520, Japan,⁵ The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China⁷

Received 1 August 2003/ Returned for modification 9 September 2003/ Accepted 13 October 2003

Adult-onset type II citrullinemia (CTLN2) is an autosomal recessive disease caused by mutations in SLC25A13, the gene encoding the mitochondrial aspartate/glutamate carrier citrin. The absence of citrin leads to a liver-specific, quantitative decrease of argininosuccinate synthetase (ASS), causing hyperammonemia and citrullinemia. To investigate the physiological role of citrin and the development of CTLN2, an Slc25a13-knockout (also known as Ctrn-deficient) mouse model was created. The resulting Ctrn^-/- mice were devoid of Slc25a13 mRNA and citrin protein. Liver mitochondrial assays revealed markedly decreased activities in aspartate transport and the malate-aspartate shuttle. Liver perfusion also demonstrated deficits in ureogenesis from ammonia, gluconeogenesis from lactate, and an increase in the lactate-to-pyruvate ratio within hepatocytes. Surprisingly, Ctrn^-/- mice up to 1 year of age failed to show CTLN2-like symptoms due to normal hepatic ASS activity. Serological measures of glucose, amino acid, and ammonia metabolism also showed no significant alterations. Nitrogen-loading treatments produced only minor changes in the hepatic ammonia and amino acid levels. These results suggest that citrin deficiency alone may not be sufficient to produce a CTLN2-like phenotype in mice. These observations are compatible, however, with the variable age of onset, incomplete penetrance, and strong ethnic bias seen in CTLN2 where additional environmental and/or genetic triggers are now suspected.

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