Molecular Genetics of Vitamin D- Dependent Hereditary Rickets

Kato, Shigeaki; Yoshizazawa, Tatsuya; Kitanaka, Susumu; Murayama, Akiko; Takeyama, Ken-ichi

doi:10.1159/000057955

Cited by 38 publications

(32 citation statements)

References 29 publications

(45 reference statements)

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“…Vitamin D receptor (VDR) (Ϫ/Ϫ) mice were generated by gene targeting as previously described (10,36). VDR genotypes were confirmed by analyzing the DNA obtained from each mouse ϳ3 wk after birth.…”

Section: Methodsmentioning

confidence: 99%

Vitamin D and phosphate regulate fibroblast growth factor-23 in K-562 cells

Ito¹,

Sakai²,

Furumoto³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

122

101

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To elucidate the precise physiological regulation of FGF-23, we characterized the mouse FGF-23 5Ј-flanking region and analyzed its promoter activity. The 5Ј-flanking region of the mouse FGF-23 gene contained a TFIID site (TATA box) and several putative transcription factor binding sites, including MZF1, GATA-1 and c-Ets-1 motifs, but it did not contain the typical sequences of the vitamin D response element. Plasmids encoding 554-bp (pGL/Ϫ0.6), 364-bp (pGL/Ϫ0.4) and 200-bp (pGL/Ϫ0.13) promoter regions containing the TFIID element and ϩ1-bp fragments drove the downstream expression of a luciferase reporter gene in transfection assays. We also found that FGF-23 mRNA was expressed in K-562 erythroleukemia cell lines but not in MC3T3-E1, Raji, or Hep G2 human carcinoma cells. Treatment with 1,25-dihydroxyvitamin D 3 in the presence of high phosphate markedly stimulated pGL/Ϫ0.6 activity, but calcium had no effect. In addition, the plasma FGF-23 levels were affected by the dietary and plasma inorganic phosphate concentrations. Finally, the levels of plasma FGF-23 in vitamin D receptor-null mice were significantly lower than in wild-type mice. The presents study demonstrated that vitamin D and the plasma phosphate level are important regulators of the transcription of the mouse FGF-23 gene. gene regulation; vitamin D receptor; phosphate homeostasis THE HOMEOSTASIS OF PLASMA PHOSPHATE is essential for many biological processes, including skeletal mineralization and energy metabolism. Recent investigations of diseases with abnormal phosphate homeostasis have revealed circulating phosphaturic hormones, collectively called phosphatonin (6, 23). Common clinical features, including hypophosphatemia resulting from renal phosphate wasting and impaired mineralization of bone are shared by X-linked hypophosphatemic rickets (XLH), tumor-induced osteomalacia (TIO), and autosomal-dominant hypophosphatemic rickets (ADHR; see Refs. 28,31,and 32), and the presence of a phosphatonin has been suspected in patients with these diseases because their plasma calcium and parathyroid hormone (PTH) levels are usually normal (8,9).Genetic studies of ADHR and TIO have identified fibroblast growth factor (FGF)-23 as a likely candidate for phosphatonin (28,31). In addition, continuous exposure to recombinant FGF-23 reproduces hypophosphatemic osteomalacia and the inappropriately low plasma levels of 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ; see Ref. 28]. Also, a mutant form of FGF-23 (FGF-23R179Q), which is derived from disease-causing missense mutations of ADHR, is resistant to proteolytic processing that normally converts the biologically functional full-length polypeptide into inactive fragments (3, 33). Furthermore, elevated circulatory levels of FGF-23 occur not only in patients with TIO but also in those with XLH (35). These findings indicate that excess FGF-23 activity causes the hypophosphatemia and impaired mineralization of bone that is associated with phosphatonin (6, 21).In a previous study, we demonstrated that the mutant FGF-23 su...

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Section: Methodsmentioning

confidence: 99%

Vitamin D and phosphate regulate fibroblast growth factor-23 in K-562 cells

Ito¹,

Sakai²,

Furumoto³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

122

101

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“…Defects in vitamin D activation and action cause different forms of vitamin D-dependent rickets whereas impaired degradation of 1,25-(OH) 2 D 3 underlies idiopathic infantile hypercalcemia (IIH). 1,2 IIH (OMIM #143880) was first described in the 1950s after an epidemic occurrence of unexplained hypercalcemia in infants receiving increased amounts of vitamin D via fortified milk products for the prevention of rickets. 3,4 Although a link to exogenous vitamin D was recognized early, the pathophysiology remained unknown until the recent identification of inactivating mutations in CYP24A1.…”

mentioning

confidence: 99%

Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia

Schlingmann

Ruminska

Kaufmann

et al. 2016

Journal of the American Society of Nephrology

227

192

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Idiopathic infantile hypercalcemia (IIH) is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis. Recently, mutations in the vitamin D catabolizing enzyme 25-hydroxyvitamin D 3 -24-hydroxylase (CYP24A1) were described that lead to increased sensitivity to vitamin D due to accumulation of the active metabolite 1,25-(OH) 2 D 3 . In a subgroup of patients who presented in early infancy with renal phosphate wasting and symptomatic hypercalcemia, mutations in CYP24A1 were excluded. Four patients from families with parental consanguinity were subjected to homozygosity mapping that identified a second IIH gene locus on chromosome 5q35 with a maximum logarithm of odds (LOD) score of 6.79. The sequence analysis of the most promising candidate gene, SLC34A1 encoding renal sodium-phosphate cotransporter 2A (NaPi-IIa), revealed autosomal-recessive mutations in the four index cases and in 12 patients with sporadic IIH. Functional studies of mutant NaPi-IIa in Xenopus oocytes and opossum kidney (OK) cells demonstrated disturbed trafficking to the plasma membrane and loss of phosphate transport activity. Analysis of calcium and phosphate metabolism in Slc34a1-knockout mice highlighted the effect of phosphate depletion and fibroblast growth factor-23 suppression on the development of the IIH phenotype. The human and mice data together demonstrate that primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25-(OH) 2 D 3 with subsequent symptomatic hypercalcemia. Clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation. Therefore, early differentiation between SLC34A1 (NaPi-IIa) and CYP24A1 (24-hydroxylase) defects appears critical for targeted therapy in patients with IIH.

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“…An increased prevalence of diabetes has been observed in vitamin D-deficient individuals (4) , and our previous study has shown that vitamin D 3 treatment restores blood glucose homeostasis in streptozotocin (STZ)-induced diabetic rats (5) . Binding of vitamin D 3 promotes the vitamin D receptor (VDR) to form a heterodimer with the retinoid X receptor and transactivates vitamin D-responsive elements present in target genes (6) . VDR mRNA and protein have previously been detected and studied in several rat tissues including liver (7,8) .…”

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confidence: 99%

Effect of vitamin D₃in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats

George¹,

Kumar

Antony

et al. 2012

Br J Nutr

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Diabetes mellitus is a growing health problem worldwide and is associated with severe liver complications. The aim of the present study is to analyse the status of metabolic and free-radical-scavenging enzymes and second messengers in the liver of streptozotocin (STZ)-induced diabetic rats, and to determine the hepatoprotective role of vitamin D 3 . All studies were performed using the liver of adult male Wistar rats. Gene expression studies were carried out using real-time PCR with specific probes. Second messenger levels were determined using 3 H-labelled Biotrak assay kits, and glucose uptake assay with D-[ 14 C]glucose. The present results show that there was a decrease in hepatic glucose uptake, malate dehydrogenase activity, glycogen content, inositol triphosphate (IP 3 ) and cyclic GMP levels, and superoxide dismutase, glutathione peroxidase, phospholipase C, cyclic AMP-responsive element-binding protein, vitamin D receptor (VDR) and insulin receptor (INSR) gene expression in the diabetic rats when compared with the controls (all P,0·05), while cyclic AMP levels and GLUT2 expression were increased (P,0·05). Treatment of the diabetic rats with vitamin D 3 and insulin reversed the altered parameters to near control values. In conclusion, the data suggest a novel role of vitamin D 3 in restoring impaired liver metabolism in STZ-induced diabetic rats by regulating glucose uptake, storage and metabolism. We demonstrated that the restoring effect of vitamin D 3 is mediated through VDR modulation, thereby improving signal transduction and controlling free radicals in the liver of diabetic rats. These data suggest a potential role for vitamin D 3 in the treatment of diabetes-associated hepatic complications.Key words: Vitamin D: Diabetes: Liver: Oxidative stress: Metabolism: Insulin Diabetes-associated complications are major causes of morbidity and mortality. The liver plays a unique role in glucose homeostasis. Because of its anatomical location, it is ideally suited to control the systemic supply of absorbed nutrients, and it is one of only two organs that both consume and produce substantial amounts of glucose. The central role of the liver in the maintenance of blood glucose levels is assured by complex regulation by metabolic substrates, insulin and other hormones (1) . Diabetes-associated hyperglycaemia and hypoinsulinaemia lead to the impairment of hepatic glucose and lipid metabolism. Virtually, the entire spectrum of liver diseases is seen in patients with diabetes, including liver cirrhosis, a significant cause of death in diabetic patients, even more relevant than CVD (2) . Interest in the development of novel antidiabetic agents has been fuelled by the intense complications due to therapeutic treatment of diabetes and associated liver failure (2,3) . An increased prevalence of diabetes has been observed in vitamin D-deficient individuals (4) , and our previous study has shown that vitamin D 3 treatment restores blood glucose homeostasis in streptozotocin (STZ)-induced diabetic rats (5) . Bind...

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Molecular Genetics of Vitamin D- Dependent Hereditary Rickets

Cited by 38 publications

References 29 publications

Vitamin D and phosphate regulate fibroblast growth factor-23 in K-562 cells

Vitamin D and phosphate regulate fibroblast growth factor-23 in K-562 cells

Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia

Effect of vitamin D₃in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats

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Molecular Genetics of Vitamin D- Dependent Hereditary Rickets

Cited by 38 publications

References 29 publications

Vitamin D and phosphate regulate fibroblast growth factor-23 in K-562 cells

Vitamin D and phosphate regulate fibroblast growth factor-23 in K-562 cells

Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia

Effect of vitamin D3in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats

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Effect of vitamin D₃in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats