Evidence for Biochemical Heterogeneity in the X-linked Hypophosphatemic Diseases

Phenotypic heterogeneity in X-linked hypophosphatemic rickets (XLH) is ascribed to variable penetrance of the genetic abnormality. However, studies of hypophosphatemic (Hyp) and gyrorotary (Gy) mice indicate that mutations at different loci along the X chromosome may underlie the genetically transmitted hypophosphatemic disorders. Thus, genetic heterogeneity may be a determinant of the phenotypic variability in XLH. To determine if such variance includes biochemical diversity, we examined whether Gy mice, similar to Hyp mice, exhibit abnormal regulation of renal 25-hydroxyvitamin D (25[OHJD)-1a-hydroxylase. Serum phosphorus in Gy (4.7±0.3 mg/dl) and phosphate (P)-depleted mice (4.9±0.4) was significantly less than normal (8.4±0.5). Consistent with P depletion, the Gy mice exhibited enhanced renal 25(OH)Dla-hydroxylase activity (9.3±0.6 fmol/mg kidney per min), similar to that of P-depleted normals (9.1±1.5), but significantly greater than that of controls (3.1±0.3). Such normal enzyme responsiveness was confirmed upon PTH stimulation (1 IU/h s.c.), which revealed that Gy mice increased renal 1-hydroxylase (59±7.7) similarly to normals (65±7.7) and Pdepleted animals (58.4±7.8). Calcitonin administration also enhanced enzyme function comparably in the animal models. Evidence confirming normally responsive calcitriol production in untreated Gy mice included increased serum 1,25-dihydroxyvitamin D levels, gastrointestinal calcium absorption, and urinary calcium. The normally regulated vitaminD metabolism in Gy mice indicates that biochemically diverse disease may result from mutations in the gene family regulating renal P transport and underlying X-linked hypophosphatemia. We suspect such heterogeneity is due to altered P transport at variable segments of the proximal convoluted tubule. (J. Clin. Invest. 1990. 85:334-339.) calcitriol - hypophosphatemia. rickets