Document Detail

Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia.
MedLine Citation:
PMID:  14701727     Owner:  NLM     Status:  MEDLINE    
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.
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
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular and cellular biology     Volume:  24     ISSN:  0270-7306     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2004 Jan 
Date Detail:
Created Date:  2003-12-31     Completed Date:  2004-02-18     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  527-36     Citation Subset:  IM    
Genetics & Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
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MeSH Terms
Amino Acids / metabolism
Ammonia / metabolism
Argininosuccinate Synthase / metabolism
Aspartic Acid / metabolism
Base Sequence
Citrullinemia / genetics*,  metabolism*
DNA / genetics
Disease Models, Animal
Liver / metabolism
Membrane Transport Proteins / deficiency*,  genetics*
Mice, Knockout
Mitochondrial Membrane Transport Proteins
Mitochondrial Proteins / deficiency*,  genetics*
NAD / metabolism
RNA, Messenger / genetics,  metabolism
Urea / metabolism
Reg. No./Substance:
0/Amino Acids; 0/Membrane Transport Proteins; 0/Mitochondrial Membrane Transport Proteins; 0/Mitochondrial Proteins; 0/RNA, Messenger; 0/SLC25A13 protein, human; 0/Slc25a13 protein, mouse; 53-84-9/NAD; 56-84-8/Aspartic Acid; 57-13-6/Urea; 7664-41-7/Ammonia; 9007-49-2/DNA; EC Synthase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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