CYP3A4 mutation causes vitamin D-dependent rickets type 3

Area of Science:

• Endocrinology
• Genetics
• Biochemistry

Background:

• Genetic forms of vitamin D-dependent rickets (VDDRs) stem from impaired vitamin D activation or receptor function.
• Existing VDDR genetic causes do not explain all cases of early-onset rickets.

Purpose of the Study:

• To identify the genetic cause in two unrelated patients with early-onset rickets and vitamin D deficiency unresponsive to treatment.
• To investigate a novel mutation in CYP3A4 as a potential cause of VDDR.

Main Methods:

• Whole exome sequencing was used to identify genetic mutations in affected patients.
• In vitro assays were performed to assess the enzymatic activity of the identified mutant CYP3A4 enzyme on vitamin D metabolites.

Main Results:

• Two patients with early-onset rickets were found to have reduced serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D.
• A recurrent de novo missense mutation (c.902T>C, p.I301T) in CYP3A4 was identified in both patients.
• The mutant CYP3A4 exhibited significantly increased activity in inactivating 1,25-dihydroxyvitamin D compared to wild-type CYP3A4 and CYP24A1.

Conclusions:

• Accelerated inactivation of vitamin D metabolites by a mutant CYP3A4 enzyme is a newly identified mechanism for vitamin D deficiency rickets.
• Mutations in CYP3A4 should be considered in the differential diagnosis of early-onset rickets.
• This finding expands our understanding of vitamin D metabolism and its regulation.