Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In humans, loss-of-function mutations in parathyroid hormone (PTH) and 25-hydroxyvitamin D3-1alpha-hydroxylase [1alpha(OH)ase] genes lead to isolated hypoparathyroidism and vitamin D-dependent rickets type I, respectively. To better understand the relative contributions of PTH and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] to skeletal and calcium homeostasis, we compared mice with targeted disruption of the PTH or 1alpha(OH)ase genes to the double null mutants. Although PTH-/- and 1alpha(OH)ase-/- mice displayed only moderate hypocalcemia, PTH-/-1alpha(OH)ase-/- mice died of tetany with severe hypocalcemia by 3 weeks of age. At 2 weeks, PTH-/- mice exhibited only minimal dysmorphic changes, whereas 1alpha(OH)ase-/- mice displayed epiphyseal dysgenesis which was most severe in the double mutants. Although reduced osteoblastic bone formation was seen in both mutants, PTH deficiency caused only a slight reduction in long bone length but a marked reduction in trabecular bone volume, whereas 1alpha(OH)ase ablation caused a smaller reduction in trabecular bone volume but a significant decrease in bone length. The results therefore show that PTH plays a predominant role in appositional bone growth, whereas 1,25(OH)2D3 acts predominantly on endochondral bone formation. Although PTH and 1,25(OH)2D3 independently, but not additively, regulate osteoclastic bone resorption, they do affect the renal calcium transport pathway cooperatively. Consequently, PTH and 1,25(OH)2D3 exhibit discrete and collaborative roles in modulating skeletal and calcium homeostasis and loss of the renal component of calcium conservation might be the major factor contributing to the lethal hypocalcemia in double mutants.
Hum Mol Genet 2005 Jun 01
PMID:Genetic models show that parathyroid hormone and 1,25-dihydroxyvitamin D3 play distinct and synergistic roles in postnatal mineral ion homeostasis and skeletal development. 1584 2

CCND2-C12orf5-FGF23-FGF6 locus at human chromosome 12p13.32 and CCND1-ORAOV1-FGF19-FGF4 locus at human chromosome 11q13.3 are paralogous regions (paralogons) within the human genome. FGF23 is the causative factor for tumor-induced osteomalacia (TIO), a paraneoplastic disorder characterized by hypophosphatemia and skeletal undermineralization, and also for autosomal dominant hypophosphatemic rickets (ADHR). Here, rat Fgf6 and Fgf23 complete coding sequences were determined by using bioinformatics. Rat Fgf6 and Fgf23 genes, consisting of three exons, were located within AC103292.6 rat genome sequence. Rat Fgf6 and Fgf23 genes were clustered in tail-to-head manner with an interval of about 52 kb. Human FGF6 and FGF23 genes were clustered in tail-to-head manner with an interval of about 54 kb. Intergenic conserved region (IGCR) within the FGF6-FGF23 gene cluster was identified based on the evolutionary conservation. Human FGF6-FGF23 IGCR (nucleotide position 111648-112242 of AC008012.8 genome sequence) and rat Fgf6-Fgf23 IGCR (nucleotide position 156318-156894 of AC103292.6 genome sequence) showed 77.6% total nucleotide identity. CP2, E47, CREB and PAX4 binding sites were conserved among human FGF6, rat Fgf6, and mouse Fgf6 promoters. GATA and E47 binding sites were conserved among human FGF23, rat Fgf23, and mouse Fgf23 promoters. Because mouse Fgf23 mRNA was expressed in dendritic cells and activated spleen, tumor infiltrating dendritic cells are candidate sources of FGF23 secretion in TIO patients. This is the first report on comparative genomics analyses on human FGF6-FGF23 gene cluster and rodents Fgf6-Fgf23 gene cluster.
Int J Mol Med 2005 Aug
PMID:Comparative genomics on mammalian Fgf6-Fgf23 locus. 1601 75

In the most recent revision of the dietary recommendations for Americans and Canadians in 1997, a recommended intake for Vitamin D was set in the absence of an estimation of mean requirements. There are now new data to estimate average requirements; however, there must be consideration of factors affecting need in populations and of total body tissue needs including the prevention and treatment of cancer. A recent study provides dietary dose-response data in the absence of sun exposure, and a mean requirement of 12.5microg (500IU) was found for Caucasian men. A seasonal build up (summer) and waning (winter) of Vitamin D stores implies that the requirement of Vitamin D in complete absence of yearly summertime sun exposure would approach levels of intake that mimic Vitamin D gained from sun exposure. High prevalence of Vitamin D insufficiency and the re-emergence of rickets have been observed worldwide. For many countries without mandatory staple food fortification, Vitamin D intake is often too low to sustain healthy circulating levels of 25 hydroxyvitamin D. Even in some countries that require (mandatory) or allow fortification (optional), Vitamin D intakes are low in some groups due to their unique dietary patterns, such as low milk consumption, vegetarian diet, limited or no use of dietary supplements, or changes away from traditional food consumption. Supplement use can significantly increase Vitamin D intakes across all age and gender groups but the benefit is primarily gained in persons whose intakes are close to adequate. African American men and women have greater prevalence of Vitamin D insufficiency, which may be a factor in their susceptibility to certain cancers. New recommendations for Vitamin D should be made for the otherwise healthy populations in greatest need of dietary Vitamin D due to lack of adequate sun exposure.
J Steroid Biochem Mol Biol 2005 Oct
PMID:Dietary recommendations to meet both endocrine and autocrine needs of Vitamin D. 1604 61

Vitamin D signaling is dependent on the availability and turnover of the active Vitamin D receptor (VDR) ligand 1,25-dihydroxycholecalciferol and on the efficiency of VDR transactivation. Activating and inactivating secosteroid metabolizing p450 enzymes, e.g. 25-hydroxylases, 1alpha-hydroxylase and 24-hydroxylase, are responsible for ligand availability on the basis of substrate production in the skin and of nutritional intake of precursors. Net availability of active hormone depends on the delivery of substrate and the balance of activating and inactivating enzymes. 1Alpha-hydroxylase is the critical activating enzyme. It is expressed in the kidney for systemic supply and in target tissues for local secosteroid activation. It is upregulated in the kidney by low calcium intake and parathyroid hormone, downregulated by phosphatonins and proinflammatory signal transduction. Transactivation of VDR depends on the correct molecule structure, effective nuclear translocation and the presence of the unliganded heterodimer partner retinoid X-receptor (RXR) and other nuclear cofactors. Rapid Vitamin D-dependent membrane associated effects and consecutive second messenger activation exert an own pattern of gene regulation. A membrane receptor for these effects is hypothesized but not yet identified. Rickets is the long known clinical syndrome of impaired Vitamin D signaling due to Vitamin D3 deficiency. It can be caused by inherited defects of the cascade, nutritional deficits, lack of sunlight exposure, malabsorption and underlying diseases like chronic inflammation. It has been shown during the last decades that many modifiers of Vitamin D signaling are targets of disease in terms of inherited and acquired syndromes and that Vitamin D signaling is modulated at multiple levels and is more complex than mere mechanistic ligand/receptor/DNA interaction.
Mol Cell Endocrinol 2006 Mar 27
PMID:Vitamin D signaling is modulated on multiple levels in health and disease. 1640 53

Vitamin D3 is synthesized in the skin during summer under the influence of ultraviolet light of the sun, or it is obtained from food, especially fatty fish. After hydroxylation in the liver into 25-hydroxyvitamin D (25(OH)D) and kidney into 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite can enter the cell, bind to the vitamin D-receptor and subsequently to a responsive gene such as that of calcium binding protein. After transcription and translation the protein is formed, e.g. osteocalcin or calcium binding protein. The calcium binding protein mediates calcium absorption from the gut. The production of 1,25(OH)2D is stimulated by parathyroid hormone (PTH) and decreased by calcium. Risk factors for vitamin D deficiency are premature birth, skin pigmentation, low sunshine exposure, obesity, malabsorption and advanced age. Risk groups are immigrants and the elderly. Vitamin D status is dependent upon sunshine exposure but within Europe, serum 25(OH)D levels are higher in Northern than in Southern European countries. Severe vitamin D deficiency causes rickets or osteomalacia, where the new bone, the osteoid, is not mineralized. Less severe vitamin D deficiency causes an increase of serum PTH leading to bone resorption, osteoporosis and fractures. A negative relationship exists between serum 25(OH)D and serum PTH. The threshold of serum 25(OH)D, where serum PTH starts to rise is about 75nmol/l according to most surveys. Vitamin D supplementation to vitamin D-deficient elderly suppresses serum PTH, increases bone mineral density and may decrease fracture incidence especially in nursing home residents. The effects of 1,25(OH)2D and the vitamin D receptor have been investigated in patients with genetic defects of vitamin D metabolism and in knock-out mouse models. These experiments have demonstrated that for active calcium absorption, longitudinal bone growth and the activity of osteoblasts and osteoclasts both 1,25(OH)2D and the vitamin D receptor are essential. On the other side, bone mineralization can occur by high ambient calcium concentration, so by high doses of oral calcium or calcium infusion. The active metabolite 1,25(OH)2D has its effects through the vitamin D receptor leading to gene expression, e.g. the calcium binding protein or osteocalcin or through a plasma membrane receptor and second messengers such as cyclic AMP. The latter responses are very rapid and include the effects on the pancreas, vascular smooth muscle and monocytes. Muscle cells contain vitamin D receptor and several studies have demonstrated that serum 25(OH)D is related to physical performance. The active metabolite 1,25(OH)2D has an antiproliferative effect and downregulates inflammatory markers. Extrarenal synthesis of 1,25(OH)2D occurs under the influence of cytokines and is important for the paracrine regulation of cell differentiation and function. This may explain that vitamin D deficiency can play a role in the pathogenesis of auto-immune diseases such as multiple sclerosis and diabetes type 1, and cancer. In conclusion, the active metabolite 1,25(OH)2D has pleiotropic effects through the vitamin D receptor and vitamin D responsive elements of many genes and on the other side rapid non-genomic effects through a membrane receptor and second messengers. Active calcium absorption from the gut depends on adequate formation of 1,25(OH)2D and an intact vitamin D receptor. Bone mineralization mainly depends on ambient calcium concentration. Vitamin D metabolites may play a role in the prevention of auto-immune disease and cancer.
Prog Biophys Mol Biol 2006 Sep
PMID:Vitamin D physiology. 1656 71

Exposure to ultraviolet radiation (UVR) is associated with both adverse and beneficial health effects. While many of the adverse effects of excessive exposure are well known, the adverse effects of insufficient UVR exposure are less clear-cut, but may include a heightened risk of several cancers and autoimmune disorders as well as of bone diseases such as rickets, osteomalacia and osteoporosis. Although some of the postulated beneficial effects of UVR exposure may occur through the maintenance of adequate levels of vitamin D, it is not clear that this can account for all of these effects. We briefly review the epidemiological literature with respect to vitamin D, UVR exposure and autoimmune diseases. We further outline alternative pathways, whereby UVR could alter the risk of development of some cancers and autoimmune disorders, independent of effects on vitamin D synthesis. Recognition of the beneficial effects of UVR exposure has led to a reconsideration of sun avoidance policies. It is important to recognize that all of the beneficial effects of UVR exposure may not occur only through UVR-induced vitamin D synthesis. Thus maintaining current sun avoidance policies while supplementing food with vitamin D may not be sufficient to avoid the risks of insufficient exposure to UVR.
Prog Biophys Mol Biol 2006 Sep
PMID:Considering the potential benefits as well as adverse effects of sun exposure: can all the potential benefits be provided by oral vitamin D supplementation? 1661 26

Phosphate homeostasis is preserved during variations in phosphate intake by short-term intrinsic renal and intestinal adaptations in transport processes, and by more long-term hormonal mechanisms, which regulate the efficiency of phosphate transport in the kidney and intestine. Recently, several phosphaturic peptides such as fibroblast growth factor 23 (FGF-23), secreted frizzled-related protein-4 (sFRP-4), extracellular phosphoglycoprotein (MEPE) and fibroblast growth factor 7 (FGF-7) have been shown to play a pathogenic role in several hypophosphatemic disorders such as tumor-induced osteomalacia (TIO), autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemic rickets (XLH), the McCune-Albright syndrome (MAS) and fibrous dysplasia (FD). These proteins induce phosphaturia and hypophosphatemia in vivo, and inhibit sodium-dependent renal phosphate transport in cultured renal epithelial cells. Interestingly, despite the induction of hypophosphatemia by FGF-23 and sFRP-4 in vivo, serum 1, 25-dihydroxyvitamin D (1alpha,25(OH)(2)D) concentrations are decreased or remain inappropriately normal, suggesting an inhibitory effect of these proteins on 25-hydroxyvitamin D 1alpha-hydroxylase activity. In FGF-23 knockout mice, 25-hydroxyvitamin D 1alpha-hydroxylase expression is increased and elevated serum 1alpha,25(OH)(2)D levels cause significant hypercalcemia and hyperphosphatemia. MEPE, however, increases circulating 1alpha,25(OH)(2)D. Circulating or local concentrations of these peptides/proteins may regulate 25-hydroxyvitamin D 1alpha-hydroxylase activity in renal tissues under physiologic circumstances.
J Steroid Biochem Mol Biol 2007 Mar
PMID:The phosphatonins and the regulation of phosphate transport and vitamin D metabolism. 1722 71

Inorganic phosphate (Pi) is fundamental to cellular metabolism and skeletal mineralization. Ingested Pi is absorbed by the small intestine, deposited in bone, and filtered by the kidney where it is reabsorbed and excreted in amounts determined by the specific needs of the organism. Two distinct renal Na-dependent Pi transporters, type IIa (NPT2a, SLC34A1) and type IIc (NPT2c, SLC34A3), are expressed in brush border membrane of proximal tubular cells where the bulk of filtered Pi is reabsorbed. Both are regulated by dietary Pi intake and parathyroid hormone. Regulation is achieved by changes in transporter protein abundance in the brush border membrane and requires the interaction of the transporter with scaffolding and signaling proteins. The demonstration of hypophosphatemia secondary to decreased renal Pi reabsorption in mice homozygous for the disrupted type IIa gene underscores its crucial role in the maintenance of Pi homeostasis. Moreover, the recent identification of mutations in the type IIc gene in patients with hereditary hypophosphatemic rickets with hypercalciuria attests to the importance of this transporter in Pi conservation and subsequent skeletal mineralization. Two novel Pi regulating genes, PHEX and FGF23, play a role in the pathophysiology of inherited and acquired hypophosphatemic skeletal disorders and studies are underway to define their mechanism of action on renal Pi handling in health and disease.
J Steroid Biochem Mol Biol 2007 Mar
PMID:Phosphate transport: molecular basis, regulation and pathophysiology. 1727 Apr 30

Vitamin D status is highly different in various countries of Europe, the Middle East and Asia. For this review, vitamin D deficiency is defined as serum 25-hydroxyvitamin D (25(OH)D) <25 nmol/l. Within European countries, serum 25(OH)D is <25 nmol/l in 2-30% of adults, increasing in the elderly and institutionalized to more than 80% in some studies. A north-south gradient was observed for serum 25(OH)D in the Euronut and MORE studies with higher levels in Scandinavia and lower levels in Italy and Spain and some Eastern European countries. This points to other determinants than sunshine, e.g. nutrition, food fortification and supplement use. Mean vitamin D intake in Scandinavia is 200-400IU/d, twice that in other European countries. Very low serum 25(OH)D levels have been reported in the Middle East, e.g. Turkey, Lebanon, Jordan and Iran. In these countries serum 25(OH)D was lower in women than in men and associated with clothing habits. In a Lebanese survey, vitamin D deficiency was observed in the majority and occurred mainly in veiled women. In India, vitamin D deficiency was observed in more than 30%, vitamin D status being poor in school children, pregnant women and large cities. Vitamin D status was much better in Malaysia and Singapore, but lower serum 25(OH)D was observed in Japan and China. Rickets and osteomalacia appear quite common in India, but precise data are lacking. Immigrants in Europe from the Middle East and Asia carry a high risk for vitamin D deficiency, pregnant women being especially at risk. Comparison of vitamin D status between countries is hampered by interlaboratory variation of serum 25(OH)D measurement. In addition, there is a need of population-based data. In conclusion, vitamin D deficiency is common in Southern Europe, the Middle East, India, China and Japan. It is less common in Northern Europe and Southeast Asia. Risk groups are young children, the elderly, pregnant women and non-western immigrants in Europe. Important determinants are skin type, sex, clothing, nutrition, food fortification, supplement use, BMI and degree of urbanization.
J Steroid Biochem Mol Biol 2007 Mar
PMID:Vitamin D status and nutrition in Europe and Asia. 1728 17

Transaldolase (TALDO) deficiency is a rare inborn error of the pentose phosphate pathway. We report the clinical presentation and laboratory findings of a new patient with TALDO deficiency. The two-year-old Arabic boy presented with neonatal onset of anemia and thrombocytopenia, tubulopathy, and rickets and was subsequently found to have cirrhosis and deafness. A comparison with other TALDO deficient patients is given.
Mol Genet Metab 2008 Jun
PMID:Transaldolase deficiency in a two-year-old boy with cirrhosis. 1833 7


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