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

TitleSlc25a13-Knockout Mice Harbor Metabolic Deficits but Fail to Display Hallmarks of Adult-Onset Type II Citrullinemia
Authors
Issue Date2004
PublisherAmerican Society for Microbiology.
Citation
Molecular And Cellular Biology, 2004, v. 24 n. 2, p. 527-536 How to Cite?
AbstractAdult-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 citruilinemia. 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.
Persistent Identifierhttp://hdl.handle.net/10722/44389
ISSN
2015 Impact Factor: 4.427
2015 SCImago Journal Rankings: 3.806
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorSinasac, DSen_HK
dc.contributor.authorMoriyama, Men_HK
dc.contributor.authorJalil, MAen_HK
dc.contributor.authorBegum, Len_HK
dc.contributor.authorLi, MXen_HK
dc.contributor.authorIijima, Men_HK
dc.contributor.authorHoriuchi, Men_HK
dc.contributor.authorRobinson, BHen_HK
dc.contributor.authorKobayashi, Ken_HK
dc.contributor.authorSaheki, Ten_HK
dc.contributor.authorTsui, LCen_HK
dc.date.accessioned2007-09-12T03:52:36Z-
dc.date.available2007-09-12T03:52:36Z-
dc.date.issued2004en_HK
dc.identifier.citationMolecular And Cellular Biology, 2004, v. 24 n. 2, p. 527-536en_HK
dc.identifier.issn0270-7306en_HK
dc.identifier.urihttp://hdl.handle.net/10722/44389-
dc.description.abstractAdult-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 citruilinemia. 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.en_HK
dc.languageengen_HK
dc.publisherAmerican Society for Microbiology.en_HK
dc.relation.ispartofMolecular and Cellular Biologyen_HK
dc.rightsCopyright © American Society for Microbiology, Molecular and cellular biology, 2004, v. 24 n. 2, p. 527-536en_HK
dc.subject.meshMitochondrial proteins - deficiency - geneticsen_HK
dc.subject.meshCitrullinemia - genetics - metabolismen_HK
dc.subject.meshMembrane transport proteins - deficiency - geneticsen_HK
dc.subject.meshNad - metabolismen_HK
dc.subject.meshRna, messenger - genetics - metabolismen_HK
dc.titleSlc25a13-Knockout Mice Harbor Metabolic Deficits but Fail to Display Hallmarks of Adult-Onset Type II Citrullinemiaen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0270-7306&volume=24&issue=2&spage=527&epage=536&date=2004&atitle=Slc25a13-Knockout+Mice+harbor+metabolic+deficits+but+fail+to+display+hallmarks+of+Adult-Onset+Type+II+Citrullinemiaen_HK
dc.identifier.emailTsui, LC: tsuilc@hkucc.hku.hken_HK
dc.identifier.authorityTsui, LC=rp00058en_HK
dc.description.naturelink_to_OA_fulltexten_HK
dc.identifier.doi10.1128/MCB.24.2.527-536.2004en_HK
dc.identifier.pmid14701727-
dc.identifier.pmcidPMC343808-
dc.identifier.scopuseid_2-s2.0-9144245537en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-9144245537&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume24en_HK
dc.identifier.issue2en_HK
dc.identifier.spage527en_HK
dc.identifier.epage536en_HK
dc.identifier.isiWOS:000188211200004-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridSinasac, DS=7801388288en_HK
dc.identifier.scopusauthoridMoriyama, M=7201454259en_HK
dc.identifier.scopusauthoridJalil, MA=36794304500en_HK
dc.identifier.scopusauthoridBegum, L=6603232432en_HK
dc.identifier.scopusauthoridLi, MX=37069508900en_HK
dc.identifier.scopusauthoridIijima, M=7201773787en_HK
dc.identifier.scopusauthoridHoriuchi, M=7202777818en_HK
dc.identifier.scopusauthoridRobinson, BH=36045175800en_HK
dc.identifier.scopusauthoridKobayashi, K=7407127141en_HK
dc.identifier.scopusauthoridSaheki, T=7005678417en_HK
dc.identifier.scopusauthoridTsui, LC=7102754167en_HK

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