Figure 127

Proposed pathogenesis of X-linked hypophosphatemic rickets (HYP). HYP, the most common defect in renal phosphate (Pi) transport, is transmitted as an X-linked dominant trait. The disorder is character-

ized by growth impairment in children, metabolic bone disease, phos-phaturia, and abnormal bioactivation of vitamin D [16]. Cell culture, parabiosis, and transplantation experiments have demonstrated that the defect in HYP is not intrinsic to the kidney but involves a circulating humoral factor other than parathyroid hormone [16,17].

Phosphate is transported across the luminal membrane of the proximal tubule by a sodium-phosphate cotransporter (NaPi). This transporter is regulated by multiple hormones. Among these is a putative phosphaturic factor that has been designated phosphatonin [18]. It is postulated that phosphatonin inhibits Pi reabsorption by way of the sodium-coupled phosphate cotransporter, and it depresses serum 1,25-dihydroxy-vitamin D3 production by inhibiting 1-a-hydroxlase activity and stimulating 24-hydroxylase activity. Positional cloning studies in families with HYP have identified a gene, designated PEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome), that is mutated in patients with X-linked hypophos-phatemia [19]. PEX, a neutral endopeptidase, presumably inactivates phosphatonin. Defective PEX activity would lead to decreased phosphatonin degradation, with excessive phosphaturia and deranged vitamin D metabolism. A similar scenario associated with increased phosphatonin production has been proposed as the basis for oncogenic hypophosphatemic osteomalacia, an acquired disorder manifested in patients with tumors of mesenchymal origin [17]. Na+—sodium ion; K+—potassium ion.

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