Hereditary 1,25-Dihydroxyvitamin D Resistant Rickets Due to a Mutation Causing Multiple Defects in Vitamin D Receptor Function

The study investigated a case of hereditary vitamin D-resistant rickets (HVDRR) in a young Saudi Arabian girl, identifying a novel homozygous mutation (I268T) in the vitamin D receptor (VDR) gene. This mutation resulted in multiple defects in VDR function, including reduced ligand binding affinity, impaired retinoid X receptor heterodimerization, and decreased coactivator binding. The I268T mutation caused a 5- to 10-fold lower affinity for 1,25-dihydroxyvitamin D(3) and required a 65-fold higher concentration for gene transactivation compared to the wild-type VDR. The study suggested that vitamin D analogs, such as 20-epi-1,25(OH)(2)D(3), could potentially restore VDR function in patients with HVDRR, as this analog improved the stability and transactivation of the I268T mutant.