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Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase
Open accessAbstract
The synthesis of bioactive vitamin D requires hydroxylation at the 1α and 25 positions by cytochrome P450 enzymes in the kidney and liver, respectively. The mitochondrial enzyme CYP27B1 catalyzes 1α-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.
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Metadata
- Authors
- Cheng, J. B., Levine, M. A., Bell, N. H., Mangelsdorf, D. J., & Russell, D. W.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2004-05-05
- Volume
- 101
- Issue
- 20
- Pages
- 7711-7715
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2011725731
- Cited by
- 762
- References
- 1
- FWCI
- 12.26
- Type
- journal article
- Language
- en
- Open access
- green
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