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- Title
CYP3A4 mutation causes vitamin D-dependent rickets type 3.
- Authors
Roizen, Jeffrey D.; Dong Li; O'Lear, Lauren; Javaid, Muhammad K.; Shaw, Nicholas J.; Ebeling, Peter R.; Nguyen, Hanh H.; Rodda, Christine P.; Thummel, Kenneth E.; Thacher, Tom D.; Hakonarson, Hakon; Levine, Michael A.; Li, Dong
- Abstract
Genetic forms of vitamin D-dependent rickets (VDDRs) are due to mutations impairing activation of vitamin D or decreasing vitamin D receptor responsiveness. Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D. Neither patient had a mutation in any genes known to cause VDDR; however, using whole exome sequencing analysis, we identified a recurrent de novo missense mutation, c.902T>C (p.I301T), in CYP3A4 in both subjects that alters the conformation of substrate recognition site 4 (SRS-4). In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1, the principal inactivator of vitamin D metabolites. As CYP3A4 mutations have not previously been linked to rickets, these findings provide insight into vitamin D metabolism and demonstrate that accelerated inactivation of vitamin D metabolites represents a mechanism for vitamin D deficiency.
- Subjects
VITAMIN D; GENETIC mutation; STEROID hormones; GENETICS; CALCIUM regulating hormones
- Publication
Journal of Clinical Investigation, 2018, Vol 128, Issue 5, p1913
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI98680