Resistance to 1,25-dihydroxyvitamin D. Association with heterogeneous defects in cultured skin fibroblasts.

Liberman, Uri; Eil, Charles; Marx, Stephen J.

doi:10.1172/jci110759

Cited by 118 publications

(46 citation statements)

References 30 publications

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“…A frequently associated and unexplained finding in HVDRR is total scalp and body alopecia (3), a feature said to be present in the more severely affected patients (4). Studies from a number of laboratories have revealed that the cause of the target organ resistance in HVDRR is a defect in the intracellular vitamin D receptor (VDR) (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

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confidence: 99%

“…It was soon demonstrated that defects in the VDR were the likely cause of the HVDRR syndrome (5) and that different families exhibited different defects (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)). An additional useful finding was the demonstration that 1,25(OH)2D3 could induce the enzyme 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) in multiple target tissues by a receptor-mediated process (27).…”

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The molecular basis of hereditary 1,25-dihydroxyvitamin D3 resistant rickets in seven related families.

Malloy¹,

Hochberg²,

Tiosano³

et al. 1990

J. Clin. Invest.

184

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Introduction Hereditary 1,25-dihydroxyvitamin D3 I1,25(OH)2D31 resistant rickets (HVDRR) is an autosomal recessive disease caused by target organ resistance to the action of 1,25(OH)1D3, the active form of the hormone. The defect in target cells is heterogenous and commonly appears to be a mutation in the gene encoding the vitamin D receptor (VDR). We have studied cultured skin fibroblasts and Epstein-Barr virus transformed lymphoblasts of seven family branches of an extended kindred having eight children affected with HVDRR. We have previously shown that cells from three affected children in this group contain an "ochre" nonsense mutation coding for a premature stop codon in exon 7 within the steroid-binding domain of the VDR gene.In The human VDR is a 50-kD protein and the cDNA has recently been cloned and sequenced (17) and found to belong to the steroid-thyroid-retinoic acid receptor superfamily of genes (18). Like the other members of this receptor family, VDR is comprised of at least two functional domains, a steroid hormone-binding domain and a DNA-binding domain (17-23). The steroid-binding domain stretches from amino acid 182 to the COOH-terminus at amino acid 427 and provides the molecule with high affinity, steroid-specific recognition of the 1,25(OH)2D3 metabolite. The DNA-binding domain, comprising amino acids 24-89, is a cysteine-rich region that contains two putative "zinc-fingers" (17). 1,25(OH)2D3 binding to the steroid-binding domain of the receptor "activates" the VDR to a form with high affinity for DNA. The DNA-binding domain of the VDR then binds to a vitamin D response element in the regulatory region of target genes to modulate transcription of responsive genes and thereby mediates hormone action (17)(18)(19)(20)(21)(22)(23).Progress to elucidate the molecular basis of HVDRR began with the demonstration that rodent skin possessed VDR (24, 25) and that cultured human dermal fibroblasts derived from skin biopsies could be used as a model system for the study of the VDR from patients (26). It was soon demonstrated that defects in the VDR were the likely cause of the HVDRR syndrome (5) and that different families exhibited different defects (5-16). An additional useful finding was the demonstration that 1,25(OH)2D3 could induce the enzyme 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) in multiple target tissues by a receptor-mediated process (27). It was subsequently found that 24-hydroxylase activity could be induced in cultured skin fibroblasts so that induction of 24-hydroxylase activity could be employed as a bioassay ofthe ability of cultured fibroblasts to respond to 1,25(OH)2D3 (5). Using this bioresponse marker, cells from a variety of patients with HVDRR

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confidence: 99%

The molecular basis of hereditary 1,25-dihydroxyvitamin D3 resistant rickets in seven related families.

Malloy¹,

Hochberg²,

Tiosano³

et al. 1990

J. Clin. Invest.

184

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“…As with many inborn errors of metabolism, HVDRD is a rare disorder; ∼70 kindreds have been described (3)(4)(5)(6)(7)(8)(9)(10) since the first publication almost 30 yr ago. The significance of the disease relates to its role in elucidating the physiology of vitamin D and calcium homeostasis in humans.…”

Section: Introductionmentioning

confidence: 99%

“…The term "hereditary hypocalcemic rickets resistant to calcitriol" defines more precisely this abnormality. However, based on our current knowledge of the etiology and pathophysiology of this disease, the term "hereditary vitamin D receptor defects" (HV-DRD) may be the most appropriate and precise to describe this condition.As with many inborn errors of metabolism, HVDRD is a rare disorder; ∼70 kindreds have been described (3)(4)(5)(6)(7)(8)(9)(10) since the first publication almost 30 yr ago. The significance of the disease relates to its role in elucidating the physiology of vitamin D and calcium homeostasis in humans.…”

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Vitamin D–Resistant Diseases

Liberman¹

2007

Journal of Bone and Mineral Research

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ABSTRACT:Hereditary vitamin D receptor defects (HVDRDs) is a more appropriate and precise title for an inborn error of metabolism commonly known as pseudo-vitamin D deficiency or vitamin D dependency, type II. It is a rare autosomal recessive disorder, ∼70 kindreds were described, but its main importance is elucidating the physiology of vitamin D and calcium homeostasis in humans. Patients usually develop the clinical and biochemical aberrations, identical to vitamin D deficiency, but with high serum levels of calcitriol, within the first year of life (i.e., muscle weakness, bone pain, deformities, and fractures). Defective calcium gut absorption leads to hypocalcemia, secondary hyperparathyroidism, hypophosphatemia, and defective mineralization of newly formed bone matrix. The disease is not cured by vitamin D replacement therapy, although some patients respond to very high doses of vitamin D or its metabolites. Cells derived from patients, mainly cultured skin fibroblasts, were used to assess steps in calcitriol action from cellular uptake to bioresponse and to elucidate the molecular aberrations in the vitamin D receptor (VDR). Point mutations in the VDR gene were identified in every patient examined, and the same defect was observed in the obligatory heterozygotes. The functional characterization of the patient's VDR reflected the localization of the mutation (18 different ones described to date), thus providing vital information about the structure-function relationship in the human VDR and the essentiality of the VDR as the mediator of vitamin D action. . These disturbances could be primary (i.e., hereditary pseudovitamin D deficiency rickets) or secondarily acquired (i.e., chronic renal failure). (2) The above title does not describe the bio-effect that characterizes the resistant state. However, the accepted term "hereditary vitamin D-resistant rickets" (HVDRR) is confusing as well, because not all causes of rickets and/or osteomalacia resistant to vitamin D or calcitriol involve primary disturbances in calcitriol metabolism or action. For example, rickets resistant to calciferol also describes primary disturbances in phosphate homeostasis as hereditary hypophosphatemic rickets with hypercalciuria (HHRH) (1) or primary bone defects such as hypophosphatasia.(2) The most helpful bio-effect to include in a description is the most direct action known to be abnormal; thus, calcium malabsorption is more useful than rickets to characterize defects in vitamin D action. The term "hereditary hypocalcemic rickets resistant to calcitriol" defines more precisely this abnormality. However, based on our current knowledge of the etiology and pathophysiology of this disease, the term "hereditary vitamin D receptor defects" (HV-DRD) may be the most appropriate and precise to describe this condition.As with many inborn errors of metabolism, HVDRD is a rare disorder; ∼70 kindreds have been described (3)(4)(5)(6)(7)(8)(9)(10) since the first publication almost 30 yr ago. The significance of the disease relates to its role in...

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“…Moreover, impaired function of macrophages in vitamin D-deficient mice was corrected in vitro by 1,25-(OH)2D3 (7). The occurrence of the syndrome of end-organ resistance to 1,25-(OH)ZD~ due to defective receptors or lack of biologic response to 1,25-(OH)*D3 (8) provides an unusual opportunity of investigating the functions of 1,25-(OH)2D3 in the immune system of the human subject. Indeed, peripheral blood mononuclear cells of patients with resistance to 1,25-(OH)2D3 did not acquire receptors for 1,25-(OH)2D3 after lectin stimulation as normal mononuclear cells do.…”

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Defective Leukocyte Fungicidal Activity in End-Organ Resistance to 1,25-Dihydroxyvitamin D

et al. 1989

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ABSTRACT. Recent studies have shown 1,25(OH)zD~ receptor-mediated modulation of leukocyte proliferation, differentiation, and function. We examined the phagocytosis and killing of microorganisms by neutrophils and monocytes from five patients of three families with hereditary resistance to 1,25(OH)2D3. Phagocytosis of microorganisms by patients' neutrophils and monocytes was normal. However, defective neutrophil killing activity toward Candida albicans (30-40% of controls) was found in all patients. The killing of Staphylococcus aureus was normal. The neutrophil chemiluminescence, nitroblue tetrazolium (NBT) dye reduction, and the generation of superoxide ions and hydrogen peroxide by neutrophils and monocytes after induction by either soluble stimuli or zymozan particles, did not differ from those in controls. The neutrophil myeloperoxidase activity was also normal. Monocytes obtained from two patients of different families before long-term calcium infusion therapy and after they became normocalcemic, demonstrated a similar impaired fungicidal activity toward Saccharomyces cerevisiae, indicating that hypocalcemia itself was not the cause of the killing defect. However, the addition of the Ca+2 ionophore A23187 (1 p M ) to the test medium restored the monocyte fungicidal activity to normal. As patients' neutrophil cytosolic free calcium concentration was similar to that in controls, it is suggested that 1,25-(OH)2D3 exerts its effect on leukocyte function by a putative receptor-mediated regulation of subcellular calcium localization which may be important for fungicidal activity. (Pediatr Res 25276-279, 1989) Abbreviations 1,25(OH)zD3, 1,25-dehydroxyvitamin D3 TPA, 12-0-tetra-decanoyl-phorbol-13-acetate f-met-leu-phe, N-formyl-L-methionyl-L-phenylalanine NBT, nitroblue-tetrazolium Recently, it has been shown that receptors for 1,25-(OH)2D3, the hormonal form of vitamin D3, are present in cellular components of the immune system and that specific functional receptors for 1 ,25-(OH)2D3 mediate the effects of 1 ,25-(OH)2D3

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Resistance to 1,25-dihydroxyvitamin D. Association with heterogeneous defects in cultured skin fibroblasts.

Cited by 118 publications

References 30 publications

The molecular basis of hereditary 1,25-dihydroxyvitamin D3 resistant rickets in seven related families.

The molecular basis of hereditary 1,25-dihydroxyvitamin D3 resistant rickets in seven related families.

Vitamin D–Resistant Diseases

Defective Leukocyte Fungicidal Activity in End-Organ Resistance to 1,25-Dihydroxyvitamin D

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