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Keywords:

  • Rickets-hereditary;
  • vitamin D receptor;
  • inborn errors in the vitamin D receptor;
  • vitamin D resistance;
  • 1,25(OH)2D (calcitriol)

Abstract

Hereditary vitamin D receptor defects (HVDRDs) is a more appropriate and precise title for an inborn error of metabolism commonly known as pseudo-vitamin D deficiency or vitamin D dependency, type II. It is a rare autosomal recessive disorder, ∼70 kindreds were described, but its main importance is elucidating the physiology of vitamin D and calcium homeostasis in humans. Patients usually develop the clinical and biochemical aberrations, identical to vitamin D deficiency, but with high serum levels of calcitriol, within the first year of life (i.e., muscle weakness, bone pain, deformities, and fractures). Defective calcium gut absorption leads to hypocalcemia, secondary hyperparathyroidism, hypophosphatemia, and defective mineralization of newly formed bone matrix. The disease is not cured by vitamin D replacement therapy, although some patients respond to very high doses of vitamin D or its metabolites. Cells derived from patients, mainly cultured skin fibroblasts, were used to assess steps in calcitriol action from cellular uptake to bioresponse and to elucidate the molecular aberrations in the vitamin D receptor (VDR). Point mutations in the VDR gene were identified in every patient examined, and the same defect was observed in the obligatory heterozygotes. The functional characterization of the patient's VDR reflected the localization of the mutation (18 different ones described to date), thus providing vital information about the structure–function relationship in the human VDR and the essentiality of the VDR as the mediator of vitamin D action.