Journal article

CYP3A4 mutation causes vitamin D-dependent rickets type 3

Jeffrey D Roizen, Dong Li, Lauren O'Lear, Muhammad K Javaid, Nicholas J Shaw, Peter R Ebeling, Hanh H Nguyen, Christine P Rodda, Kenneth E Thummel, Tom D Thacher, Hakon Hakonarson, Michael A Levine

JOURNAL OF CLINICAL INVESTIGATION | AMER SOC CLINICAL INVESTIGATION INC | Published : 2018

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 C..

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University of Melbourne Researchers

Grants

Awarded by NIH


Awarded by EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT


Awarded by NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES


Awarded by NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES


Funding Acknowledgements

We thank Brian Phillips for help examining vitamin D metabolites and Harsh Kanwar for assistance in performing assays. This study was supported in part by grants from the NIH (R01 DK079970 and R01 DK112955 to MAL; K08 HD087964 to JDR), the Children's Hospital of Philadelphia Research Institute (to MAL), and the Institutional Development Fund to the Center for Applied Genomics from the Children's Hospital of Philadelphia (to HH). MKJ was supported by the National Institute of Health Research (NIHR) Oxford Biomedical Research Centre (BRC).