A recurrent de novo missense mutation in CYP3A4 (c.902T>C) was identified in two patients with early-onset rickets, resulting in a 10-fold greater oxidation of 1,25-dihydroxyvitamin D in vitro.
Case Report (n=2)
Accelerated inactivation of vitamin D metabolites by a CYP3A4 mutation represents a novel mechanism for vitamin D deficiency and early-onset rickets.
Effect estimate: 10-fold greater activity
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.
Angellotti et al. (Fri,) conducted a case report in early-onset rickets (n=2). CYP3A4 c.902T>C (p.I301T) mutation vs. WT CYP3A4 was evaluated on 1,25-dihydroxyvitamin D oxidation activity in vitro (10-fold greater activity). A recurrent de novo missense mutation in CYP3A4 (c.902T>C) was identified in two patients with early-onset rickets, resulting in a 10-fold greater oxidation of 1,25-dihydroxyvitamin D in vitro.