Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia.

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.
Authors	David S Sinasac, Mitsuaki Moriyama, M Abdul Jalil, Laila Begum, Meng Xian Li, Mikio Iijima, Masahisa Horiuchi, Brian H Robinson, Keiko Kobayashi, Takeyori Saheki, Lap-Chee Tsui
Journal	Molecular and cellular biology (Mol Cell Biol) Vol. 24 Issue 2 Pg. 527-36 (Jan 2004) ISSN: 0270-7306 [Print] United States
PMID	14701727 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Amino Acids Membrane Transport Proteins Mitochondrial Membrane Transport Proteins Mitochondrial Proteins RNA, Messenger SLC25A13 protein, human Slc25a13 protein, mouse NAD Aspartic Acid Ammonia Urea DNA Argininosuccinate Synthase
Topics	Amino Acids (metabolism) Ammonia (metabolism) Animals Argininosuccinate Synthase (metabolism) Aspartic Acid (metabolism) Base Sequence Citrullinemia (genetics, metabolism) DNA (genetics) Disease Models, Animal Female Gluconeogenesis Humans Liver (metabolism) Male Membrane Transport Proteins (deficiency, genetics) Mice Mice, Knockout Mitochondrial Membrane Transport Proteins Mitochondrial Proteins (deficiency, genetics) Mutation NAD (metabolism) Phenotype RNA, Messenger (genetics, metabolism) Urea (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!