Genetic disorders and defects in vitamin d action

Abstract

Two rare genetic diseases can cause rickets in children. The critical enzyme to synthesize calcitriol from 25-hydroxyvitamin D, the circulating hormone precursor, is 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-hydroxylase). When this enzyme is defective and calcitriol can no longer be synthesized, the disease 1alpha-hydroxylase deficiency develops. The disease is also known as vitamin D-dependent rickets type 1 or pseudovitamin D deficiency rickets. When the VDR is defective, the disease hereditary vitamin D-resistant rickets, also known as vitamin D-dependent rickets type 2, develops. Both diseases are rare autosomal recessive disorders characterized by hypocalcemia, secondary hyperparathyroidism, and early onset severe rickets. In this article, these 2 genetic childhood diseases, which present similarly with hypocalcemia and rickets in infancy, are discussed and compared.

Fig. 1

Missense mutations identified in patients with 1α-hydroxylase deficiency. The human 1α-hydroxylase enzyme is composed of 508 amino acids. The locations of the missense mutations are shown above the line. Depicted below line are the names of the α helices (open boxes), the meander sequence (M, grey box); the cysteine pocket (CP, hatched box); substrate recognition sites (SRS, black boxes) and the β turns.

Fig. 2

Missense mutations identified in patients with HVDRR. (A) The locations of missense mutations in the VDR DNA binding-domain depicted as a two-zinc finger structure. (B) The locations of the missense mutations in the VDR ligand-binding domain are shown above the line. The filled rectangles represent α helices (H1–H12) and the hatched box represents the β sheet structure. The location of the E1 and AF-2 domains are also indicated.