PHEX gene and
hypophosphatemia.
X-linked hypophosphatemia (XLH) and
tumor-induced osteomalacia (TIO) are diseases that have in common abnormal proximal renal tubular function resulting in increased renal clearance of inorganic
phosphorus and
hypophosphatemia. The recent discovery of the PHEX gene has provided new insights to these disorders. In this regard, identification of the PHEX gene product as a membrane-bound
endopeptidase suggests that the pathophysiologic cascade underlying XLH likely involves inactivation mutations of the gene causing a failure to clear an active
hormone, phosphatonin, from the circulation. The presence of this
hormone through unknown mechanisms decreases the
sodium-dependent
phosphate cotransporter in the kidney, resulting in impaired
phosphate transport. In contrast, TIO likely evolves secondary to
tumor overproduction of the putative phosphatonin, which exerts physiologic function despite efforts to counteract the resultant
hypophosphatemia with overproduction of PHEX transcripts that are insufficient to accommodate the enhanced substrate load. These potential pathophysiologic mechanisms for XLH and TIO provide valuable inroads to understanding
phosphate homeostasis, as well as
vitamin D metabolism, bone mineralization, and
calcium metabolism.