The first step in vitamin D3 activation requires 25-hydroxylation of vitamin D3 (or vitamin D2), mediated by vitamin D 25-hydroxylase (CYP2R1). Defects in CYP2R1 can cause rickets, vitamin D-dependent 1B (VDDR1B; MIM:600081), a disorder caused by a selective deficiency of the active form of vitamin D (CTL) resulting in defective bone mineralization and clinical features of rickets. The missense mutation L99P can cause VDDR1B (Cheng et al. 2004, Casella et al. 2004). When plasma levels of 25-hydroxyvitamin D3 (calcidiol, CDL) are low, classic symptoms of vitamin D deficiency, including skeletal abnormalities, hypocalcemia, and hypophosphatemia, are observed.