Identification of a Novel Nonsense Mutation in the Ligand-Binding Domain of the Vitamin D Receptor Gene and Clinical Description of Two Greek Patients with Hereditary Vitamin D-Resistant Rickets and Alopecia

Abstract

Background/Aims: We analyzed the vitamin D receptor (VDR) gene in 2 Greek patients who exhibited the classical features of hereditary vitamin D-resistant rickets (HVDRR) type II, including severe bone deformities and alopecia. We also describe the clinical phenotypes and the response to treatment of our patients. Methods: Genomic DNA was extracted from peripheral blood samples of both patients. Coding region and flanking introns of VDR gDNA was amplified and direct sequenced. Results: A unique cytosine to thymine (C>T) transition was identified at nucleotide position 1066 (c.1066C>T) in the ligand-binding domain of the VDR gene of both patients, predicting the substitution of a glutamine to a terminal codon at position 356 (Gln356stop). Conclusions: The novel nonsense mutation c.1066C>T (Gln356stop) is expected to result in a VDR protein 71 amino acids shorter and thus to affect the normal VDR function. In particular, the missing protein part alters the VDR heterodimerization with the retinoid X receptor which has been correlated with the presence of alopecia. Both patients were introduced to treatment with supraphysiological doses of 1α-calcidiol which improved their clinical phenotypes except for alopecia.

The Molecular Basis of Calcium and Phosphorus Inherited Metabolic Disorders

“…Numerous studies have shown that alopecia is not correlated with Ca 2+ or Vitamin D levels, but is associated with the dysfunctional receptor, supporting the role of the receptor in several metabolic pathways. It has been proposed that mutations, affecting DNA binding or RXR heterodimerization cause alopecia, while mutations that prevent the binding of 1,25(OH) 2 D 3 or coactivators to the receptor are not associated with alopecia [ 98 , 99 , 100 ]. The biochemical findings include hypocalcaemia, hypophosphatemia, secondary hyperparathyroidism and elevated elevated levels of serum 1,25(OH) 2 D 3 and ALP.…”