PMID:14701727

Citation	Sinasac, DS, Moriyama, M, Jalil, MA, Begum, L, Li, MX, Iijima, M, Horiuchi, M, Robinson, BH, Kobayashi, K, Saheki, T and Tsui, LC (2004) Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia. Mol. Cell. Biol. 24:527-36
Abstract	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.
Links	PubMed PMC343808
Keywords	Amino Acids/metabolism; Ammonia/metabolism; Animals; Argininosuccinate Synthase/metabolism; Aspartic Acid/metabolism; Base Sequence; Citrullinemia/genetics; Citrullinemia/metabolism; DNA/genetics; Disease Models, Animal; Female; Gluconeogenesis; Humans; Liver/metabolism; Male; Membrane Transport Proteins/deficiency; Membrane Transport Proteins/genetics; Mice; Mice, Knockout; Mitochondrial Membrane Transport Proteins; Mitochondrial Proteins/deficiency; Mitochondrial Proteins/genetics; Mutation; NAD/metabolism; Phenotype; RNA, Messenger/genetics; RNA, Messenger/metabolism; Urea/metabolism
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