SLC5A2 Gene: SGLT2 Function, Mutations, and Clinical Significance

The SLC5A2 gene encodes the sodium/glucose cotransporter 2 (SGLT2), a low-affinity, high-capacity transporter primarily expressed in the proximal tubule of the kidney. SGLT2 is responsible for reabsorbing approximately 90% of filtered glucose from the glomerular filtrate back into the bloodstream, coupling glucose transport to the sodium gradient. This gene is of major clinical importance as the target of SGLT2 inhibitors (e.g., empagliflozin, dapagliflozin), which are used to treat type 2 diabetes, heart failure, and chronic kidney disease. Loss-of-function mutations in SLC5A2 cause familial renal glucosuria, a benign condition characterized by persistent glucosuria without hyperglycemia.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• SGLT2-mediated glucose reabsorption in proximal tubule (Reactome: R-HSA-429182)

• Sodium/glucose cotransporter activity in kidney (KEGG: hsa04964 - Proximal tubule bicarbonate reclamation

• but SGLT2 is not directly listed; use GO-based pathway)

• Carbohydrate absorption (KEGG: hsa04973 - Carbohydrate digestion and absorption

• includes SGLT1 but SGLT2 is not a major player)

SGLT2 is a 672-amino acid membrane protein with 14 transmembrane helices. It belongs to the SLC5 family of sodium-coupled cotransporters. The protein couples the downhill influx of sodium to the uphill transport of glucose across the apical membrane of proximal tubular cells. It has a high capacity but low affinity for glucose (Km ~2 mM). SGLT2 is the primary mediator of renal glucose reabsorption, and its inhibition by drugs like canagliflozin and empagliflozin reduces blood glucose in diabetic patients. The protein is also expressed in other tissues at low levels, but its renal function is the most clinically relevant.