Glucose-Galactose Malabsorption (GGM) is characterized by a neonatal onset of a several diarrhea that results in death unless the offending sugars are removed from the diet. It is caused by a defect in the brush border Na/glucose cotransporter (SGLT1). We have identified the transporter, cloned and mapped the gene, and found the mutations responsible for the disease in 33 patients. The goal now is to understand the molecular and cell biology of GGM. We plan to: continue screening new patients for mutations; determine how the mutations cause the malabsorption; devise new therapies to treat patients; and resolve whether or not carriers of GGM mutations have impaired glucose absorption. New patients will be screened using genomic DNA, PCR-amplification of exons, single strand conformational polymorphism (SSCP) gels, and sequencing. 90 percent of the mutations are in the gene coding region and result in the production of mutant and truncated proteins. Our hypothesis is that the truncated proteins are defective and that mutant proteins are not inserted into the plasma membrane. We will test this hypothesis by expressing mutants in Xenopus laevis oocytes an using electrophysiological, immunological, biochemical and microscopic techniques. Once the reason for impaired sugar transport is determined in the model expression system, we will test this in biopsy samples from the patients. In those cases where mutations cause a defect in trafficking SGLT1 protein between the endoplasmic reticulum and the plasma membrane, we will devise strategies to increase the delivery of SGLT1 to the plasma membrane. Finally, in kindreds where we have identified GGM mutations, we will screen family members for heterozygotes and normal homozygotes. Sugar absorption will be measured using H-breath tests to determine if carriers exhibit any symptoms of malabsorption. This study will enable us to identify and treat patients with sugar malabsorption due to mutations in the SGLT1 gene, and will provide unique information about the synthesis, trafficking and function of the cotransporter.
| Wright, Ernest M; Loo, Donald D F; Hirayama, Bruce A et al. (2004) Surprising versatility of Na+-glucose cotransporters: SLC5. Physiology (Bethesda) 19:370-6 |
| Wright, Ernest M; Turk, Eric (2004) The sodium/glucose cotransport family SLC5. Pflugers Arch 447:510-8 |
| Zampighi, Guido A; Kreman, Michael; Lanzavecchia, Salvatore et al. (2003) Structure of functional single AQP0 channels in phospholipid membranes. J Mol Biol 325:201-10 |
| Diez-Sampedro, Ana; Hirayama, Bruce A; Osswald, Christina et al. (2003) A glucose sensor hiding in a family of transporters. Proc Natl Acad Sci U S A 100:11753-8 |
| Veenstra, M; Turk, E; Wright, E M (2002) A ligand-dependent conformational change of the Na+/galactose cotransporter of Vibrio parahaemolyticus, monitored by tryptophan fluorescence. J Membr Biol 185:249-55 |
| Quick, Matthias; Wright, Ernest M (2002) Employing Escherichia coli to functionally express, purify, and characterize a human transporter. Proc Natl Acad Sci U S A 99:8597-601 |
| Wright, Ernest M; Turk, Eric; Martin, Martin G (2002) Molecular basis for glucose-galactose malabsorption. Cell Biochem Biophys 36:115-21 |
| le Coutre, Johannes; Turk, Eric; Kaback, H Ronald et al. (2002) Ligand-induced differences in secondary structure of the Vibrio parahaemolyticus Na+/galactose cotransporter. Biochemistry 41:8082-6 |
| Meinild, A K; Loo, D D; Hirayama, B A et al. (2001) Evidence for the involvement of Ala 166 in coupling Na(+) to sugar transport through the human Na(+)/glucose cotransporter. Biochemistry 40:11897-904 |
| Wright, E M (2001) Renal Na(+)-glucose cotransporters. Am J Physiol Renal Physiol 280:F10-8 |
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