A new metabolic path in type 3 rickets

TL;DR

A new type of rickets is caused by a gain-of-function mutation in the CYP3A4 enzyme, leading to the production of an inactive vitamin D metabolite.

Contribution

The discovery of a gain-of-function mutation in CYP3A4 as the cause of type 3 rickets introduces a novel mechanism in rickets pathology.

Findings

Type 3 rickets is caused by a CYP3A4 (Ile301Thr) gain-of-function mutation.

The mutation leads to the production of the inactive vitamin D metabolite 11α,25(OH)2D3.

This finding opens a new research direction in understanding rickets.

Abstract

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.

Rickets, a bone disorder, was historically categorised into either nutritional (vitamin D deficiency) or genetic forms involving loss‐of‐function mutations in mineral metabolism. Recently, a new mechanism, type 3 rickets, was discovered to be caused by a gain‐of‐function mutation in CYP3A4 (Ile301Thr). This mutant enzyme generates a previously unknown inactive vitamin D metabolite, 11α,25(OH)2D3, leading to 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.

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