565 A BRUSH BORDER MEMBRANE DEFECT IN PHOSPHATE TRANSPORT I IN X-LINKED HYPOPHOSPHATEMIA

Abstract

Stability of genes on the X chromosome during evolution and homologous mutant phenotypes in human X-linked hypophosphatemia (XLH), and Hyp mouse convinced us to study phosphate (Pi) transport in the latter to delineate the mutant gene product. Net reabsorption of Pi in the Hyp/Y (hemizygous) mouse is impaired in vivo. The defect in transepithelial transport of anion is not dependent on PTH. Hyp/Y cortex slices which expose the basolateral membrane take up and efflux Pi and incorporate anion into cellular pools normally. Accordingly neither “transport run out” nor “metabolic run out” of Pi, from the cytosol pool in equilibrium with luminal Pi across the brush border membrane, are affected in the mutant phenotype. Brush-border membrane vesicles (BBMV) purified ten fold from normal renal cortex transport Pi against an electrochemical gradient by an Na⁺-dependent, arsenate-inhibited process; an Na⁺-independent diffusional process is also present. Hyp/Y BBMVs have a partial deletion of the Na⁺-dependent Pi transport process (Hyp/Y, 227 pmoles/mg protein at 60s; +/Y littermate control, 408 pmoles/mg; p <0.001). Time-course studies confirm a significant loss of Na⁺-dependent Pi transport in Hyp/Y at 30 and 60s, 2 min, 10 and 30 min. Simultaneous transport of D-glucose is normal in Hyp/Y BBMV. We conclude that the mutant gene product which impairs transepithelial transport of Pi in XLH is a Pi carrier located in the brush border membrane.

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