Molecular genetics of the human Na⁺/glucose cotransporter

Summary

Recent success in expression cloning has revealed the primary structure of the Na⁺/glucose cotransporter from rabbit small intestine, and this has subsequently led to the cloning of the Na⁺/glucose cotransporters from human small intestine and human kidney. Close homology is evident between the rabbit and human intestinal Na⁺/glucose cotransporters at the DNA level, and the predicted amino acid and secondary structure levels. The Na⁺/glucose cotransporter amino acid sequence from human kidney is 57% identical with that from human small intestine. Significant homology also exists between these Na⁺/glucose cotransporters and theE. coli Na⁺/proline cotransporter (putP). The rabbit intestinal Na⁺/glucose cotransporter has 11 potential membrane spanning regions and 2 hydrophilic regions containing highly charged residues. The amino acid sequence shows two potential N-glycosylation sites (N-X-T/S). Using an in vitro translation approach we were able to determine that only one of these (Asn 248) is glycosylated. Expression experiments withXenopus oocytes using the N-glycosylation inhibitor tunicamycin indicate that glycosylation of Asn 248 is required for functional expression of the transporter. The N-X-T/S sequence at Asn 248 is conserved in the human intestinal and the human renal Na⁺/glucose cotransporter. Chromosomal localization studies map the human intestinal Na⁺/glucose cotransporter gene (SGLT1) to the q11.2→qter region of chromosome 22 and the human renal Na⁺/glucose cotransporter gene (SGLT2) to the q-arm of chromosome 16. Thus the intestinal and renal Na⁺/glucose cotransporters are encoded by different genes located on different chromosomes. This is consistent with the observation that inherited defects of the transporters, intestinal glucose/galactose malabsorption and renal glycosuria, do not appear to be genetically linked.