CYP3A4 mutation causes vitamin D-dependent rickets type 3

J Clin Invest. 2018 May 1;128(5):1913-1918. doi: 10.1172/JCI98680. Epub 2018 Apr 3.


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.

Keywords: Bone Biology; Bone disease; Genetic diseases; Genetics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcitriol* / genetics
  • Calcitriol* / metabolism
  • Cytochrome P-450 CYP3A* / genetics
  • Cytochrome P-450 CYP3A* / metabolism
  • Exome*
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Mutation*
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism
  • Rickets* / enzymology
  • Rickets* / genetics
  • Vitamin D / analogs & derivatives*
  • Vitamin D / genetics
  • Vitamin D / metabolism
  • Vitamin D3 24-Hydroxylase / genetics
  • Vitamin D3 24-Hydroxylase / metabolism
  • Whole Genome Sequencing


  • Receptors, Calcitriol
  • VDR protein, human
  • Vitamin D
  • 25-hydroxyvitamin D
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • CYP24A1 protein, human
  • Vitamin D3 24-Hydroxylase
  • Calcitriol