Characterization of the null murine sodium/myo-inositol cotransporter 1 (Smit1 or Slc5a3) phenotype: myo-inositol rescue is independent of expression of its cognate mitochondrial ribosomal protein subunit 6 (Mrps6) gene and of phosphatidylinositol levels in neonatal brain

Mol Genet Metab. Sep-Oct 2008;95(1-2):81-95. doi: 10.1016/j.ymgme.2008.05.008.


Ablation of the murine Slc5a3 gene results in severe myo-inositol (Ins) deficiency and congenital central apnea due to abnormal respiratory rhythmogenesis. The lethal knockout phenotype may be rescued by supplementing the maternal drinking water with 1% Ins. In order to test the hypothesis that Ins deficiency leads to inositide deficiencies, which are corrected by prenatal treatment, we measured the effects of Ins rescue on Ins, phosphatidylinositol (PtdIns) and myo-inositol polyphosphate levels in brains of E18.5 knockout fetuses. As the Slc5a3 gene structure is unique in the sodium/solute cotransporter (SLC5) family, and exon 1 is shared with the mitochondrial ribosomal protein subunit 6 (Mrps6) gene, we also sought to determine whether expression of its cognate Mrps6 gene is abnormal in knockout fetuses. The mean level of Ins was increased by 92% in brains of rescued Slc5a3 knockout fetuses (0.48 versus 0.25 nmol/mg), but was still greatly reduced in comparison to wildtype (6.97 nmol/mg). The PtdIns, InsP(5) and InsP(6) levels were normal without treatment. Mrps6 gene expression was unaffected in the E18.5 knockout fetuses. This enigmatic model is not associated with neonatal PtdIns deficiency and rescue of the phenotype may be accomplished without restoration of Ins. The biochemical mechanism that both uniformly leads to death and allows for Ins rescue remains unknown. In conclusion, in neonatal brain tissue, Mrps6 gene expression may not be contingent on function of its embedded Slc5a3 gene, while inositide deficiency may not be the mechanism of lethal apnea in null Slc5a3 mice.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apnea / embryology
  • Apnea / genetics
  • Apnea / metabolism*
  • Apnea / pathology
  • Brain / embryology
  • Brain / metabolism*
  • Brain / pathology
  • Gene Expression*
  • Humans
  • Inositol / metabolism*
  • Mice
  • Mice, Knockout
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Molecular Sequence Data
  • Phenotype
  • Phosphatidylinositols / metabolism*
  • Phylogeny
  • Ribosomal Proteins / chemistry
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism*
  • Sequence Alignment
  • Spinal Cord
  • Symporters / chemistry
  • Symporters / deficiency*
  • Symporters / genetics
  • Vertebrates / classification
  • Vertebrates / genetics


  • Mitochondrial Proteins
  • Mrps6 protein, mouse
  • Phosphatidylinositols
  • Ribosomal Proteins
  • SLC5A3 protein, mouse
  • Symporters
  • Inositol