Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia.
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.
Sinasac
David S
DS
Genetics & Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
Moriyama
Mitsuaki
M
Jalil
M Abdul
MA
Begum
Laila
L
Li
Meng Xian
MX
Iijima
Mikio
M
Horiuchi
Masahisa
M
Robinson
Brian H
BH
Kobayashi
Keiko
K
Saheki
Takeyori
T
Tsui
Lap-Chee
LC
D000596:Amino Acids / Q000378:metabolism; D000641:Ammonia / Q000378:metabolism; D000818:Animals; D001124:Argininosuccinate Synthase / Q000378:metabolism; D001224:Aspartic Acid / Q000378:metabolism; D001483:Base Sequence; D020159:Citrullinemia / Q000235:genetics* / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005943:Gluconeogenesis; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics*; D009154:Mutation; D009243:NAD / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014508:Urea / Q000378:metabolism
D000596:Amino Acids; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C119629:SLC25A13 protein, human; C492277:Slc25a13 protein, mouse; D009243:NAD; D001224:Aspartic Acid; D000641:Ammonia; D014508:Urea; D004247:DNA; D001124:Argininosuccinate Synthase