期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 5, 页码 1913-1918出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI98680
关键词
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资金
- NIH [R01 DK079970, R01 DK112955, K08 HD087964]
- Children's Hospital of Philadelphia Research Institute
- Institutional Development Fund
- National Institute of Health Research (NIHR) Oxford Biomedical Research Centre (BRC)
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.
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