title: Genetic disorders of Vitamin D biosynthesis and degradation.
abstract: Vitamin D, an inactive secosteroid pro-hormone, is produced by the action of ultraviolet light on 7-dehydrocholesterol in the skin. The active hormone, 1,25(OH)2D is produced by sequential 25-hydroxylation in the liver, principally by CYP2R1, and 1α-hydroxylation in the kidney by CYP27B1. Mutations in CYP27B1 cause 1α-hydroxylase deficiency, also known as vitamin D dependent rickets type I or hereditary pseudo-vitamin D deficient rickets; very rare mutations in CYP2R1 can cause 25-hydroxylase deficiency. Both deficiencies cause hypocalcemia, secondary hyperparathyroidism, severe rickets in infancy, and low serum concentrations of 1,25(OH)2D; both disorders respond to hormonal replacement therapy with calcitriol. The inactivation of vitamin D is principally initiated by its 23- and 24-hydroxylation by CYP24A1. Mutations in CYP24A1 can cause both severe neonatal hypercalcemia and a less severe adult hypercalcemic syndrome. Other pathways of vitamin D metabolism are under investigation, notably its 20-hydroxylation by the cholesterol side-chain cleavage enzyme, CYP11A1.
authors.affiliation: Center for Reproductive Sciences and Department of Pediatrics, HSE 1634, University of California San Francisco, San Francisco, CA 94143-0556, USA. Electronic address: wlmlab@ucsf.edu.
authors.forename: Walter L
authors.initials: WL
authors.lastname: Miller
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics*; D000818:Animals; D002117:Calcitriol / Q000737:chemistry; D049109:Cell Proliferation; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics*; D002784:Cholesterol / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D000072467:Cytochrome P450 Family 2 / Q000235:genetics*; D004252:DNA Mutational Analysis; D003684:Dehydrocholesterols / Q000378:metabolism; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics; D051379:Mice; D009154:Mutation; D051381:Rats; D012279:Rickets / Q000175:diagnosis / Q000235:genetics; D013256:Steroids / Q000378:metabolism; D014466:Ultraviolet Rays; D014807:Vitamin D / Q000096:biosynthesis* / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics*
chemical_list: D003684:Dehydrocholesterols; D013256:Steroids; D014807:Vitamin D; D002784:Cholesterol; C016705:7-dehydrocholesterol; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; C000600378:CYP27B1 protein, human; D002786:Cholesterol Side-Chain Cleavage Enzyme; D002117:Calcitriol
keywords: CYP24A1; CYP27B1; CYP2R1; Calcium; Neonatal hypercalcemia; Rickets; Secosteroid