Alternative titles; symbols
HGNC Approved Gene Symbol: SLC5A3
Cytogenetic location: 21q22.11 Genomic coordinates (GRCh38) : 21:34,073,578-34,106,260 (from NCBI)
In addition to serving as the precursor of phosphatidylinositol, the major inositol-containing phospholipid, and phosphatidylinositol-4,5-bisphosphate, a key molecule in cellular signal transduction, myoinositol plays an important role in osmoregulation. In certain mammalian renal and brain cells, myoinositol transport and levels are controlled by extracellular osmolality or tonicity. The millimolar levels of myoinositol in most mammalian cells or tissues are 5- to 500-fold higher than the micromolar concentrations in extracellular fluid. The highest levels are found in certain regions of the brain, but with an inexplicable microregional variation. Cerebrospinal fluid levels are higher than those in the blood due to a combination of de novo synthesis in brain capillary pericytes, concentrative uptake at the choroid plexus, and limited transport capacity across the blood-brain barrier. A Na(+)/myoinositol cotransporter cDNA (SLC5A3) was cloned from canine renal cells and sequenced by Kwon et al. (1992). The SLC5A3 protein is number 3 of the solute carrier family 5 and was initially designated SMIT.
Berry et al. (1995) cloned the human SLC5A3 gene and showed that its sequence consists of a single intronless open reading frame of 2,157-bp. The predicted 718-amino acid protein is highly homologous to the product of the canine SLC5A3 gene. The authors found expression of SLC5A3 in many tissues, including brain. They commented that the inability of a trisomic 21 cell to downregulate expression of 3 copies of this osmoregulatory gene could result in increased flux of both myoinositol and sodium ion across the plasma membrane. The potential consequences include perturbations in the cell membrane potential and tissue osmolyte levels. Thus, Berry et al. (1995) concluded that the SLC5A3 gene may play a role in the pathogenesis of Down syndrome.
Berry et al. (1996) found that an expressed sequence tag EST00541 is part of the SLC5A3 gene.
Using fluorescence in situ hybridization, Berry et al. (1995) localized the SLC5A3 gene to chromosome 21q22.
Berry et al. (2003) developed mice deficient in Smit by targeted disruption. Shaldubina et al. (2006) used these mice to show that depletion of brain myoinositol in Smit heterozygous mice had no effect on lithium-sensitive behavior. Shaldubina et al. (2006) remarked that their findings, taken together with their previous work showing that Smit-null mice have an even greater depletion of inositol in brain with no reduction in phosphatidylinositol levels, are difficult to reconcile with the current formulation of the inositol depletion hypothesis.
Berry, G. T., Mallee, J. J., Blouin, J.-L., Antonarakis, S. E. The 21q22.1 STS marker, VNO2 (EST00541 cDNA), is part of the 3-prime sequence of the human Na(+)/myo-inositol cotransporter (SLC5A3) gene. Cytogenet. Cell Genet. 73: 77-78, 1996. [PubMed: 8646889] [Full Text: https://doi.org/10.1159/000134311]
Berry, G. T., Mallee, J. J., Kwon, H. M., Rim, J. S., Mulla, W. R., Muenke, M., Spinner, N. B. The human osmoregulatory Na(+)/myo-inositol cotransporter gene (SLC5A3): molecular cloning and localization to chromosome 21. Genomics 25: 507-513, 1995. [PubMed: 7789985] [Full Text: https://doi.org/10.1016/0888-7543(95)80052-n]
Berry, G. T., Wu, S., Buccafusca, R., Ren, J., Gonzales, L. W., Ballard, P. L., Golden, J. A., Stevens, M. J., Greer, J. J. Loss of murine Na+/myo-inositol cotransporter leads to brain myo-inositol depletion and central apnea. J. Biol. Chem. 278: 18297-18302, 2003. [PubMed: 12582158] [Full Text: https://doi.org/10.1074/jbc.M213176200]
Kwon, H. M., Yamauchi, A., Uchida, S., Preston, A. S., Garcia-Perez, A., Burg, M. B., Handler, J. S. Cloning of the cDNA for a Na(+)/myo-inositol cotransporter, a hypertonicity stress protein. J. Biol. Chem. 267: 6297-6301, 1992. [PubMed: 1372904]
Shaldubina, A., Johanson, R. A., O'Brien, W. T., Buccafusca, R., Agam, G., Belmaker, R. H., Klein, P. S., Bersudsky, Y., Berry, G. T. SMIT1 haploinsufficiency causes brain inositol deficiency without affecting lithium-sensitive behavior. Molec. Genet. Metab. 88: 384-388, 2006. [PubMed: 16644257] [Full Text: https://doi.org/10.1016/j.ymgme.2006.03.007]