Preparing your results

Our searching services are busy right now. Your search will reload in five seconds.

Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia.

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.

Pubmed ID: 17035501


  • Lindhurst MJ
  • Fiermonte G
  • Song S
  • Struys E
  • De Leonardis F
  • Schwartzberg PL
  • Chen A
  • Castegna A
  • Verhoeven N
  • Mathews CK
  • Palmieri F
  • Biesecker LG


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

October 24, 2006

Associated Grants

  • Agency: LSPPPO CDC HHS, Id: LS-45039
  • Agency: Intramural NIH HHS, Id:

Mesh Terms

  • Anemia
  • Animals
  • Anion Transport Proteins
  • Central Nervous System
  • Embryo Loss
  • Embryo, Mammalian
  • Ketoglutaric Acids
  • Membrane Transport Proteins
  • Mice
  • Mice, Knockout
  • Mitochondria
  • Mitochondrial Proteins
  • Mutation
  • Thiamine Pyrophosphate