A new metabolic path in type 3 rickets

Rickets, a disorder of bone formation, was originally known as nutritional rickets due to vitamin D deficiency. Advances in science have since identified various genetic forms, typically involving loss-of-function mutations in vitamin D activation or other mineral metabolism pathways. Recently, type 3 rickets was identified as a previously undescribed gain-of-function mutation in CYP3A4 (Ile301Thr). This mutant enzyme leverages the unique features of cytochrome P450 to produce an inactive vitamin D metabolite, 11α,25(OH)₂D₃, resulting in insufficient active vitamin D. The discovery of this unique gain-of-function aetiology and its associated metabolite opens a significant new direction in rickets research.