Vitamin-D-Dependent Rickets Type II

Brooks, Marion H.; Bell, Norman H.; Love, Leon; Stern, Paula H.; Orfei, Emilio; Queener, Sherry F.; Hamstra, Alan J.; DeLuca, Hector F.

doi:10.1056/nejm197805042981804

Cited by 310 publications

(35 citation statements)

References 19 publications

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“…A similar cross talk mechanism was proposed for PXR/constitutive androstane receptor and VDR (Drocourt et al, 2002). Such regulatory overlap may have implications for treatment of conditions in which the function of a hormonal nuclear receptor is altered, such as the thyroid hormone resistance syndrome, linked to mutations in TR (Sakurai et al, 1989), or vitamin D-resistant rickets, in which a mutated VDR does not respond to Vit D 3 (Brooks et al, 1978). If orphan nuclear receptors in the presence of specific therapeutic agents increased the expression of genes that are normally regulated by the defective hormonal nuclear receptor, this could provide a paradigm for amelioration of specific clinical or physiologic manifestations of these conditions.…”

Section: Levothyroxine Upregulates P-gpmentioning

confidence: 99%

Levothyroxine Up-Regulates P-Glycoprotein Independent of the Pregnane X Receptor

Mitin¹,

Moltke²,

Court³

et al. 2004

Drug Metab Dispos

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ABSTRACT:P-Glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) constitute a physiologic barrier in the intestine for many of the same substrates. Their expression can be influenced by nuclear receptor NR1I2 (pregnane X receptor; PXR), which acts as a receptor for various endobiotics and xenobiotics. However, P-gp and CYP3A4 are not identical in anatomic localization, suggesting unique as well as shared regulatory mechanisms of gene expression. We

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Section: Levothyroxine Upregulates P-gpmentioning

confidence: 99%

Levothyroxine Up-Regulates P-Glycoprotein Independent of the Pregnane X Receptor

Mitin¹,

Moltke²,

Court³

et al. 2004

Drug Metab Dispos

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“…Whatever the basic molecular defect(s), the accumulating data clearly show a great heterogeneity in the clinical features ofpatients with hereditary resistance to 1,25(OH)2D and in their response to therapy with vitamin D derivatives (1). Favorable clinical responses to the administration ofpharmacological doses of native vitamin D, 25(OH)D3, la(OH)D3, 1,25(OH)2D3 (3)(4)(5)(6)(7)(8)(9)(10), or 24,25(OH)2D3 (11) have been reported in some patients. However, it has been shown that other patients with resistance to 1,25(0H)2D3 may remain unresponsive to similar therapeutic trials (10,12,13) or, after prolonged remission oftheir symptoms, become completely refractory to treatment with vitamin D derivatives (10).…”

Section: Introductionmentioning

confidence: 99%

Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D.

Balsan¹,

Garabédian²,

Larchet³

et al. 1986

J. Clin. Invest.

253

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We report the beneficial effects of calcium infusions in a child with hereditary resistance to 1,25(OH)2D and alopecia. This patient after transient responsiveness to vitamin D derivatives became unresponsive to all therapy despite serum 1,25(OH)2D concentrations maintained at levels -100-fold normal. A 7-mo trial with calcium infusions led to correction of biochemical abnormalities and healing of rickets. Bone biopsies (n = 3) showed a normal mineralization and the disappearance of the osteomalacia. Cultures of bone-derived cells demonstrated a lack of activation of 25-hydroxyvitamin D 24-hydroxylase and osteocalcin synthesis by 1,25(0H)2D3 (10-' and 10' M). These results demonstrate that (a) even in the absence of a normal 1,25(OH)2D3 receptor-effector system in bone cells, normal mineralization can be achieved in humans if adequate serum calcium and phosphorus concentrations are maintained; and (b) calcium infusions may be an efficient alternative for the management of patients with this condition who are unresponsive to large doses of vitamin D derivatives.

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“…The importance of a functional receptor is clearly demonstrated through the disease vitamin D-dependent rickets type II (5,6). Patients with this disease suffer impaired calcium absorption despite high circulating levels of 1,25-dihydroxyvitamin D3.…”

mentioning

confidence: 99%

Structure and regulation of the rat 1,25-dihydroxyvitamin D3 receptor.

Burmester

Wiese

Maeda

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

108

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Complementary DNA clones encoding the entire rat 1,25-dihydroxyvitamin D3 receptor were isolated, and the total 423-amino acid sequence was deduced. The amino acid sequence of the rat receptor is similar but not identical to the reported human receptor sequence. The cysteine-rich DNA-binding domain is completely conserved and the steroidbinding domain is >93% conserved between rat and human. The cDNA was used as a probe in blot analysis of polyadenylylated RNA to show that the 1,25-dihydroxyvitamin D3 receptor mRNA is a single 4.4-kilobase mRNA that is expressed in intestine and kidney, slightly expressed in heart, and not detectable in liver and spleen. The receptor mRNA concentration is markedly increased during development of the rat intestine between day 14 and day 21, in accord with previous results obtained by measurement of receptor concentration by ligand binding or immunoblotting.The primary function of 1,25-dihydroxyvitamin D3, the active form of vitamin D, is to increase serum calcium and phosphorus (1, 2). The action of 1,25-dihydroxyvitamin D3 is mediated through an intracellular receptor protein that is present in target tissues at a very low concentration, -0.001% (3,4). This receptor binds 1,25-dihydroxyvitamin D3 and then interacts with specific sites in chromatin, resulting in specific gene transcription. These gene products then effect calcium transport in the intestine and cause calcium mobilization from bone and calcium reabsorption in kidney (1,2).The importance of a functional receptor is clearly demonstrated through the disease vitamin D-dependent rickets type II (5, 6). Patients with this disease suffer impaired calcium absorption despite high circulating levels of 1,25-dihydroxyvitamin D3. A defective receptor has been reported to be the cause in at least some kindrids (7).Monoclonal antibodies against the receptor have been isolated (8). The receptor has a molecular weight of 55,000 when identified by these antibodies on an immunoblot (9, 10). A partial cDNA for the rat receptor was isolated by screening a kidney Agtll expression library with these antibodies (11). When expressed in Escherichia coli, this cDNA produced a region of the receptor capable of specifically binding 1,25-dihydroxyvitamin D3, confirming the authenticity of the clone. In addition, a partial cDNA for the avian receptor (12) and the complete cDNA for the human receptor (13) have been sequenced.We report here the nucleotide sequence and the predicted amino acid sequence for the complete rat receptor. § Comparison of the rat sequence to the human sequence shows that the receptor has remained highly conserved between the two species. The cloned cDNA was used to study the regulation of receptor gene transcription. A single 4.4-kilobase (kb) receptor mRNA is expressed in the intestine, kidney, and heart of adult rats. This mRNA is not detectable in preparations isolated from intestine of 14-day-old rat, but by day 21, it has increased substantially.MATERIALS AND METHODS RNA Isolation. RNA was prepared by the pr...

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Vitamin-D-Dependent Rickets Type II

Cited by 310 publications

References 19 publications

Levothyroxine Up-Regulates P-Glycoprotein Independent of the Pregnane X Receptor

Levothyroxine Up-Regulates P-Glycoprotein Independent of the Pregnane X Receptor

Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D.

Structure and regulation of the rat 1,25-dihydroxyvitamin D3 receptor.

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