Mutations in the vitamin D receptor and hereditary vitamin D-resistant rickets

Abstract

Heterogeneous loss of function mutations in the vitamin D receptor (VDR) interfere with vitamin D signaling and cause hereditary vitamin D-resistant rickets (HVDRR). HVDRR is characterized by hypocalcemia, secondary hyperparathyroidism and severe early-onset rickets in infancy and is often associated with consanguinity. Affected children may also exhibit alopecia of the scalp and total body. The children usually fail to respond to treatment with calcitriol; in fact, their endogenous levels are often very elevated. Successful treatment requires reversal of hypocalcemia and secondary hyperparathyroidism and is usually accomplished by administration of high doses of calcium given either intravenously or sometimes orally to bypass the intestinal defect in VDR signaling.

Figure 1

Variations in patterns of scalp hair in children with alopecia. (a) Total alopecia, (b) areas of normal hair adjacent to bald areas, (c and d) different patterns of alopecia despite the children having the same VDR mutation, and (e) child with a full head of hair despite severe hypocalcemia and rickets. Figure from Mol Cell Endocrinol 2011; 347:90–96 used with permission.

Figure 2

Mutations in the VDR that cause HVDRR. (a) Location of mutations in the DNA-binding domain (DBD). Conserved amino acids are shaded. (b) Location of mutations in the ligand-binding domain (LBD). The α-helices are shown as black boxes and the β-turns as hatched box. Missense mutations are on top and nonsense mutations on bottom. E1 and AF-2 (activation function 2) represent helices important for transactivation; adapted from Feldman et al.