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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

Authors

  • 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

Journal

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

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