G832A single nucleotide mutation in human SLC22A11 in osteoporosis patient attenuates transport properties of estrone sulfate conjugates

초록

Estrogen is known to be the key hormone for maintenance of bone mass, and estrogen deficiency is the major cause of age-related bone loss in humans. Estrogen deficiency also induces an imbalance in bone remodeling, which accelerates loss of bone mass and increases the risk of fracture. Therefore, we screen SNP and function characterization of SLC22A11, a steroid sulfate transporter, in female osteoporosis patients and a control group in the Korean women osteoporosis group, using the Xenopus oocyte expression system. From 50 healthy subjects and 50 subjects with osteoporosis we found three single mutations in SLC22A11 using GC-clamped DGGE. Among them one non-synonymous SNP was found in osteoporosis group (G832A results in E278K). We prepare E278K mutant of SLC22A11 and investigated its transport properties. The uptake of [³H] estrone sulfate via mutant E278K was reduced when compared with wild-type SLC22A11. The Km value for wild type and E278K was 0.7 and 1.2 µM, and the Vmax for wild-type and E278K was 1.8 and 0.47 pmol/oocyte/h, respectively. The present study demonstrates that SLC22A11 variants are causing to inter-individual variations that is leading to the differences in anionic drug disposition and perhaps used as a marker to certain disease including osteoporosis.