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

2014 ◽  
Vol 82 (3) ◽  
pp. 206-212 ◽  
Author(s):  
Anna Papadopoulou ◽  
Evangelia Bountouvi ◽  
Evangelia Gole ◽  
Artemis Doulgeraki ◽  
Symeon Tournis ◽  
...  
Keyword(s):  
Vitamin D ◽  
Ligand Binding ◽  
Vitamin D Receptor ◽  
Nonsense Mutation ◽  
Receptor Gene ◽  
Binding Domain ◽  
Vitamin D Receptor Gene ◽  
Vitamin D Resistant Rickets ◽  
Clinical Description ◽  
Resistant Rickets

scholarly journals Mutations in the Vitamin D Receptor Gene in Three Kindreds Associated with Hereditary Vitamin D Resistant Rickets

1997 ◽  
Vol 82 (9) ◽  
pp. 3156-3160 ◽  
Author(s):  
Fiona J. Cockerill ◽  
Nigar S. Hawa ◽  
Nasim Yousaf ◽  
Martin Hewison ◽  
Jeffrey L H. O’Riordan ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Receptor Gene ◽  
Vitamin D Receptor Gene ◽  
Vitamin D Resistant Rickets ◽  
Resistant Rickets

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

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 5106-5114 ◽  
Author(s):  
Peter J. Malloy ◽  
Rong Xu ◽  
Lihong Peng ◽  
Sara Peleg ◽  
Abdullah Al-Ashwal ◽  
...  
Keyword(s):  
Vitamin D ◽  
Ligand Binding ◽  
Vitamin D Receptor ◽  
Novel Mutation ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Retinoid X Receptor ◽  
Vdr Gene ◽  
Dihydroxyvitamin D3 ◽  
Resistant Rickets

Abstract Hereditary vitamin D-resistant rickets (HVDRR) is an autosomal recessive disease caused by mutations in the vitamin D receptor (VDR). We studied a young Saudi Arabian girl who exhibited the typical clinical features of HVDRR, but without alopecia. Analysis of her VDR gene revealed a homozygous T to C mutation in exon 7 that changed isoleucine to threonine at amino acid 268 (I268T). From crystallographic studies of the VDR ligand-binding domain, I268 directly interacts with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and is involved in the hydrophobic stabilization of helix H12. We recreated the I268T mutation and analyzed its effects on VDR function. In ligand binding assays, the I268T mutant VDR exhibited an approximately 5- to 10-fold lower affinity for [3H]1,25(OH)2D3 compared with the wild-type (WT) VDR. The I268T mutant required approximately a 65-fold higher concentration of 1,25(OH)2D3 to be equipotent in gene transactivation. Both retinoid X receptor heterodimerization and coactivator binding were reduced in the I268T mutant. Analogs of 1,25(OH)2D3 have been proposed as potential therapeutics for patients with HVDRR. Interestingly, in protease sensitivity assays, treatment with the potent vitamin D analog, 20-epi-1,25(OH)2D3, stabilized I268T mutant proteolytic fragments better than 1,25(OH)2D3. Moreover, 20-epi-1,25(OH)2D3 restored transactivation of the I268T mutant to levels exhibited by WT VDR treated with 1,25(OH)2D3. In conclusion, we describe a novel mutation, I268T, in the VDR ligand-binding domain that alters ligand binding, retinoid X receptor heterodimerization, and coactivator binding. These combined defects in VDR function cause resistance to 1,25(OH)2D3 action and result in the syndrome of HVDRR.

A homozygous mutation in the DNA binding domain of human vitamin D receptor causes vitamin D resistant rickets

Bone ◽  
2012 ◽  
Vol 50 ◽  
pp. S43
Author(s):  
B.C. van der Eerden⁎ ◽  
J.C. van der Heyden ◽  
J.P. van Hamburg ◽  
M. Schreuders-Koedam ◽  
P.S. Asmawidjaja ◽  
...  
Keyword(s):  
Vitamin D ◽  
Dna Binding ◽  
Vitamin D Receptor ◽  
Binding Domain ◽  
Homozygous Mutation ◽  
Dna Binding Domain ◽  
Vitamin D Resistant Rickets ◽  
Resistant Rickets
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