Positional cloning of the PEX gene: new insights into the pathophysiology of X-linked hypophosphatemic rickets.

X-linked hypophosphatemic rickets (HYP) is the most common form of hereditary renal phosphate wasting. The hallmarks of this disease are isolated renal phosphate wasting with inappropriately normal calcitriol concentrations and a mineralization defect in bone. Studies in the Hyp mouse, one of the murine models of the human disease, suggest that there is an approximately 50% decrease in both message and protein of NPT-2, the predominant sodium-phosphate cotransporter in the proximal tubule. However, human NPT-2 maps to chromosome 5q35, indicating that it is not the disease gene. Positional cloning studies have led to the identification of a gene, PEX, which is responsible for the disorder. Further studies have led to identification of the murine Pex gene, which is mutated in the murine models of the disorder. These studies, in concert with other studies, have led to improved understanding of the pathophysiology of HYP and a new appreciation for the complexity of normal phosphate homeostasis.