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rdf:type |
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lifeskim:mentions |
umls-concept:C0000768,
umls-concept:C0002871,
umls-concept:C0013935,
umls-concept:C0015127,
umls-concept:C0039848,
umls-concept:C0243070,
umls-concept:C0333668,
umls-concept:C0521451,
umls-concept:C0927232,
umls-concept:C1314792,
umls-concept:C1422628
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pubmed:issue |
43
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pubmed:dateCreated |
2006-10-25
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pubmed:abstractText |
SLC25A19 mutations cause Amish lethal microcephaly (MCPHA), which markedly retards brain development and leads to alpha-ketoglutaric aciduria. Previous data suggested that SLC25A19, also called DNC, is a mitochondrial deoxyribonucleotide transporter. We generated a knockout mouse model of Slc25a19. These animals had 100% prenatal lethality by embryonic day 12. Affected embryos at embryonic day 10.5 have a neural-tube closure defect with ruffling of the neural fold ridges, a yolk sac erythropoietic failure, and elevated alpha-ketoglutarate in the amniotic fluid. We found that these animals have normal mitochondrial ribo- and deoxyribonucleoside triphosphate levels, suggesting that transport of these molecules is not the primary role of SLC25A19. We identified thiamine pyrophosphate (ThPP) transport as a candidate function of SLC25A19 through homology searching and confirmed it by using transport assays of the recombinant reconstituted protein. The mitochondria of Slc25a19(-/-) and MCPHA cells have undetectable and markedly reduced ThPP content, respectively. The reduction of ThPP levels causes dysfunction of the alpha-ketoglutarate dehydrogenase complex, which explains the high levels of this organic acid in MCPHA and suggests that mitochondrial ThPP transport is important for CNS development.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-10222232,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-10562540,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-10830166,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-11226231,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-11708858,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-12185364,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-12376931,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-12411483,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-12788927,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-13679382,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-14519855,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-15539640,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-15888483,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-16120340,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-7853374,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-8363582,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-8592459,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-8930410,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-9405644,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17035501-9500544
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
0027-8424
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pubmed:author |
pubmed-author:BieseckerLeslie GLG,
pubmed-author:CastegnaAlessandraA,
pubmed-author:ChenAmyA,
pubmed-author:De LeonardisFrancescoF,
pubmed-author:FiermonteGiuseppeG,
pubmed-author:LindhurstMarjorie JMJ,
pubmed-author:MathewsChristopher KCK,
pubmed-author:PalmieriFerdinandoF,
pubmed-author:SchwartzbergPamela LPL,
pubmed-author:SongShiweiS,
pubmed-author:StruysEduardE,
pubmed-author:VerhoevenNandaN
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pubmed:issnType |
Print
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pubmed:day |
24
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pubmed:volume |
103
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
15927-32
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:17035501-Anemia,
pubmed-meshheading:17035501-Animals,
pubmed-meshheading:17035501-Anion Transport Proteins,
pubmed-meshheading:17035501-Central Nervous System,
pubmed-meshheading:17035501-Embryo, Mammalian,
pubmed-meshheading:17035501-Embryo Loss,
pubmed-meshheading:17035501-Ketoglutaric Acids,
pubmed-meshheading:17035501-Membrane Transport Proteins,
pubmed-meshheading:17035501-Mice,
pubmed-meshheading:17035501-Mice, Knockout,
pubmed-meshheading:17035501-Mitochondria,
pubmed-meshheading:17035501-Mitochondrial Proteins,
pubmed-meshheading:17035501-Mutation,
pubmed-meshheading:17035501-Thiamine Pyrophosphate
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pubmed:year |
2006
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pubmed:articleTitle |
Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia.
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pubmed:affiliation |
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. marjr@mail.nih.gov
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural,
Research Support, N.I.H., Intramural
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