A Rationale for Treatment of Hereditary Vitamin D-resistant Rickets with Analogs of 1α,25-Dihydroxyvitamin D3

Abstract

Hereditary vitamin D-resistant rickets (HVDRR) is caused by heterogeneous inactivating mutations in the vitamin D receptor (VDR). Treatment of HVDRR patientswith high doses of oral calcium and supraphysiologic doses of 1␣,25-dihydroxyvitamin D 3 (1,25D 3 ) has had limited success. In this study we explored the use of vitamin D analogs as a potential therapy for this disorder. The rationale for the use of vitamin D analogs is that they bind the VDR at different amino acid residues than 1,25D 3 , and their ability to modulate VDR functions differs from that of the natural hormone. In this report, we examined the VDR from three HVDRR patients with mutations in the ligand-binding domain of the VDR (histidine 305 to glutamine, arginine 274 to leucine, and phenylalanine 251 to cysteine) for their responses to two vitamin D analogs, 20-epi-1,25D 3 and 1␤-hydroxymethyl-3-epi-16-ene-26a,27a-bishomo-25D 3 (JK-1626-2). Our results reveal that vitamin D analogs partially or completely restore the responsiveness of the mutated VDR. Analog treatment seemed to be more successful when the mutation affects the amino acids directly involved in ligand binding rather than amino acids that contribute to a functional VDR interface with dimerization partners or coactivators of transcription. Hereditary vitamin D-resistant rickets (HVDRR)1 is an autosomal recessive disorder characterized by end-organ resistance to 1␣,25-dihydroxyvitamin D 3 (1,25D 3 ) (1, 2). Clinically, the syndrome is recognized by severe early onset rickets with bowing of the lower extremities, short stature, and often alopecia (2-5). Resistance to 1,25D 3 in HVDRR leads to impaired intestinal calcium absorption. This results in a series of metabolic abnormalities including frank hypocalcemia, secondary hyperparathyroidism, elevated alkaline phosphatase levels, hypophosphatemia, and markedly increased 1,25D 3 levels (2). Treatment of HVDRR patients with high doses of oral calcium and supraphysiologic doses of 1,25D 3 has had limited success. More aggressive therapy to bypass the defect in intestinal calcium absorption is long term intravenous infusion of calcium that restores the serum calcium levels to normal and reverses the rickets in some cases (2, 5-7). However, this approach has the usual complications associated with intravenous therapy, and its use has been limited because of its complexity.The resistance to 1,25D 3 in HVDRR is caused by heterogeneous mutations in the nuclear receptor for vitamin D (2, 8, 9). Therefore, this disease emphasizes the importance of vitamin D receptor (VDR)-mediated action of 1,25D 3 in skeletal development and bone mineralization as well as in the development of hair follicles. Like other members of the nuclear receptor superfamily, the VDR is activated by binding to its ligand (1,25D 3 ), and its action is mediated through distinct functional domains for DNA binding, ligand binding, and transcriptional activation (10, 11). HVDRR patients with mutations in the DNA binding domain of VDR do not respond to 1,25D 3 treatment mainly...

Rescue of MODY-1 by Agonist Ligands of Hepatocyte Nuclear Factor-4α

“…2c) may result from both displacement of an endogenous-bound agonist complemented by direct suppression of transactivation by bound antagonist ligand. This view may further indicate the means for treating selected MODY-1 subjects by excess HNF-4␣ agonist ligands or by selective drugs designed to restore transcriptional activity by protein-ligand complementation (42,43).…”

2.ALPHA.-(3-Hydroxypropyl)- and 2.ALPHA.-(3-Hydroxypropoxy)-1.ALPHA.,25-dihydroxyvitamin D3 Accessible to Vitamin D Receptor Mutant Related to Hereditary Vitamin D-Resistant Rickets.

“…The trypsin-resistant fragments were detected by autoradiography. 7) We found that O1C3 stabilized the mutant VDR conformation twice as well, and the analogue O2C3 stabilized the mutant VDR conformation 10-times as well as 1a,25(OH) 2 D 3 (Fig. 3).…”

“…We propose that this design strategy would provide a potential therapeutic approach for treatment of genetic disease. [7][8][9] …”

“…5) Recently, Peleg et al have demonstrated the rationale for using A ring-modified analogues to restore loss of binding and transcriptional activity of the Arg274Leu mutant. 7) Another study, by Koh et al extended these findings by examination of steroidal and nonsteroidal vitamin D mimics for their ability to restore activities of this mutant VDR. 8,9) This prompted us to report our preliminary results on two analogues, O1C3 and O2C3 that appear to bind the VDR mutant Arg274Ala in which, similarly to Arg274Leu, the amino acid substitution causes a hydrophobic hole that prohibits the 1a-OH group of 1a,25(OH) 2 D 3 from forming hydrogen bond to the LBD of VDR.…”

The Hypocalcemic Disorders

“…Although as discussed above, recently developed analogs of vitamin D have not been generally recommended for therapy of hypocalcemia, two novel analogs (20-Epi-1,25(OH) 2 D 3 and JK-1626-2) have been found to be somewhat more efficacious than calcitriol in the treatment of cases of hereditary resistance to vitamin D (HVDRR) caused by mutations in the ligand-binding domain of VDR [125].…”