title: Normal regulation of calcitriol production in Gy mice. Evidence for biochemical heterogeneity in the X-linked hypophosphatemic diseases.
abstract: 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[OH]D)-1 alpha-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)D-1 alpha-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 P-depleted 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 vitamin D 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.
authors: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
authors: G A
authors: GA
authors: Davidai
authors: T
authors: T
authors: Nesbitt
authors: M K
authors: MK
authors: Drezner
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000032:analysis; D000818:Animals; D002117:Calcitriol / Q000096:biosynthesis*; D002118:Calcium / Q000378:metabolism; D007015:Hypophosphatemia, Familial / Q000235:genetics*; D007408:Intestinal Absorption; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D010281:Parathyroid Hormone / Q000494:pharmacology; D010710:Phosphates / Q000097:blood*; D014807:Vitamin D / Q000378:metabolism; D014960:X Chromosome
chemical_list: D010281:Parathyroid Hormone; D010710:Phosphates; D014807:Vitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002118:Calcium