Cyp2r1, cytochrome P450 2R1, is the principal hepatic 25-hydroxylase responsible for the hydroxylation of parent vitamin D to 25-hydroxyvitamin D [25(OH)D], a major circulating metabolite of vitamin D reflecting vitamin D status [1,2,3]. It is crucial in the vitamin D metabolic pathway [4]. Serum 25(OH)D levels were reduced by more than 50% in Cyp2r1 -/- knockout mice compared to wild-type mice, demonstrating its importance in maintaining normal 25(OH)D levels [1].

Inactivating mutations in CYP2R1 can lead to a novel form of vitamin D-deficiency rickets, classified as vitamin D dependent rickets type 1B (VDDR1B, MIM 600081) [1]. Missense mutations (L99P and K242N) in affected members of some Nigerian families with rickets were found. In vitro studies of the mutant CYP2R1 proteins in HEK293 cells showed normal expression levels but completely absent or markedly reduced 25-hydroxylase activity by the L99P and K242N mutations, respectively [1].

In conclusion, Cyp2r1 is essential in the vitamin D metabolic pathway for the hydroxylation of vitamin D to 25(OH)D. Studies using Cyp2r1 knockout mouse models and human mutation analysis have revealed its role in maintaining vitamin D status and its association with a specific form of vitamin D-deficiency rickets. Understanding Cyp2r1 function provides insights into the mechanisms of vitamin D-related disorders and may contribute to the development of better treatment strategies for such diseases.