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Hereditary 1,25-dihydroxyvitamin D resistant rickets due to a mutation causing multiple defects in vitamin D receptor
Peter J Malloy1, Rong Xu, Lihong Peng
1Division of Endocrinology, Gerontology and Metabolism, Stanford University School of Medicine, Stanford University Medical Center, Room S025, Stanford, California 94305-5103, USA. malloy@cmgm.stanford.edu
Endocrinology
|August 17, 2004
Summary
Hereditary vitamin D-resistant rickets (HVDRR) is caused by vitamin D receptor (VDR) mutations. A novel I268T VDR mutation impairs 1,25(OH)2D3 binding and function, offering therapeutic insights.
Area of Science:
- Endocrinology
- Molecular Genetics
- Biochemistry
Background:
- Hereditary vitamin D-resistant rickets (HVDRR) is a rare genetic disorder.
- It stems from mutations in the vitamin D receptor (VDR) gene, leading to impaired vitamin D signaling.
- Understanding VDR mutations is crucial for developing targeted therapies.
Observation:
- A Saudi Arabian girl presented with HVDRR symptoms but lacked alopecia.
- Genetic analysis identified a novel homozygous T to C mutation in exon 7 of the VDR gene (I268T).
- This mutation affects isoleucine at amino acid position 268 in the VDR ligand-binding domain.
Findings:
- The I268T VDR mutation significantly reduced the affinity for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) by 5-10 fold.
- Higher concentrations of 1,25(OH)2D3 were required for gene transactivation with the mutant VDR.
- Retinoid X receptor (RXR) heterodimerization and coactivator binding were diminished in the I268T mutant VDR.
Implications:
- The I268T mutation disrupts VDR function, causing resistance to 1,25(OH)2D3.
- Novel vitamin D analogs, such as 20-epi-1,25(OH)2D3, show potential therapeutic benefits.
- These analogs can stabilize the mutant VDR and restore its transactivation function, offering new treatment strategies for HVDRR.