title: Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.
abstract: The synthesis of bioactive vitamin D requires hydroxylation at the 1 alpha and 25 positions by cytochrome P450 enzymes in the kidney and liver, respectively. The mitochondrial enzyme CYP27B1 catalyzes 1 alpha-hydroxylation in the kidney but the identity of the hepatic 25-hydroxylase has remained unclear for >30 years. We previously identified the microsomal CYP2R1 protein as a potential candidate for the liver vitamin D 25-hydroxylase based on the enzyme's biochemical properties, conservation, and expression pattern. Here, we report a molecular analysis of a patient with low circulating levels of 25-hydroxyvitamin D and classic symptoms of vitamin D deficiency. This individual was found to be homozygous for a transition mutation in exon 2 of the CYP2R1 gene on chromosome 11p15.2. The inherited mutation caused the substitution of a proline for an evolutionarily conserved leucine at amino acid 99 in the CYP2R1 protein and eliminated vitamin D 25-hydroxylase enzyme activity. These data identify CYP2R1 as a biologically relevant vitamin D 25-hydroxylase and reveal the molecular basis of a human genetic disease, selective 25-hydroxyvitamin D deficiency.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Cheng
authors.forename: Michael A
authors.initials: MA
authors.lastname: Levine
authors.forename: Norman H
authors.initials: NH
authors.lastname: Bell
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.forename: David W
authors.initials: DW
authors.lastname: Russell
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D002112:Calcifediol / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D053493:Cholestanetriol 26-Monooxygenase; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D000072467:Cytochrome P450 Family 2; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D014808:Vitamin D Deficiency / Q000378:metabolism / Q000503:physiopathology
chemical_list: D013250:Steroid Hydroxylases; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002112:Calcifediol