Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase

Jeffrey B. Cheng, Michael A. Levine, Norman H. Bell, David J. Mangelsdorf, David W. Russell

Research output: Contribution to journalArticlepeer-review

488 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)7711-7715
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number20
StatePublished - May 18 2004
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • General


Dive into the research topics of 'Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase'. Together they form a unique fingerprint.

Cite this