With recognition that vitamin D is the precursor for 1,25- dihydroxyvitamin D, it has become possible to characterize defects in the activation (1-dehydroxylation) of vitamin D and defects in the target action of activated (1,25-dihydroxy) vitamin D. We have demonstrated a broad spectrum of manifestations of hereditary resistance to 1,25 (OH)2D ranging from infantile rickets with alopecia and no intestinal response to calciferols to adult onset osteomalacia with satisfactory intestinal response to high doses of calciferols and with no epidermal abnormalities. This syndrome usually results from a mutation in the gene for the vitamin D receptor. Skin fibroblasts from all subjects with hereditary resistance to 1,25(OH)2D display abnormalities in this effector system, and defects in many discrete steps of this pathway have been identified with these cells. Cells with mutations in the 1,25(OH)2D effector pathway can be used to explore mechanisms of calciferol action. They have been used to establish that the 1,25(OH)2D receptor mediates an extremely rapid (1-3 minutes) rise of cyclic GMP in response to 1,25(OH)2D3 and that certain receptor mutations compromise many receptor functions but allow another function to be retained normally. This establishes that 1,25(OH)2D receptors couple to different responses by distinct mechanisms.
