The Experts below are selected from a list of 12876 Experts worldwide ranked by ideXlab platform
Eli Sprecher - One of the best experts on this subject based on the ideXlab platform.
-
familial tumoral calcinosis from characterization of a rare phenotype to the pathogenesis of ectopic calcification
Journal of Investigative Dermatology, 2010Co-Authors: Eli SprecherAbstract:Familial tumoral calcinosis (FTC) refers to a heterogeneous group of inherited disorders characterized by the occurrence of cutaneous and subcutaneous calcified masses. Two major forms of the disease are now recognized. Hyperphosphatemic FTC has been shown to result from mutations in three genes: fibroblast growth factor-23 (FGF23), coding for a potent phosphaturic protein, KL encoding Klotho, which serves as a co-receptor for FGF23, and GALNT3, which encodes a glycosyltransferase responsible for FGF23 O-glycosylation; defective function of any one of these three proteins results in Hyperphosphatemia and ectopic calcification. The second form of the disease is characterized by absence of metabolic abnormalities, and is, therefore, termed normophosphatemic FTC. This variant was found to be associated with absence of functional SAMD9, a putative tumor suppressor and anti-inflammatory protein. The data gathered through the study of these rare disorders have recently led to the discovery of novel aspects of the pathogenesis of common disorders in humans, underscoring the potential concealed within the study of rare diseases.
-
familial tumoral calcinosis and the role of o glycosylation in the maintenance of phosphate homeostasis
Biochimica et Biophysica Acta, 2009Co-Authors: Ilana Chefetz, Eli SprecherAbstract:Familial tumoral calcinosis refers to a group of disorders inherited in an autosomal recessive fashion. Hyperphosphatemic tumoral calcinosis is characterized by increased re-absorption of phosphate through the renal proximal tubule, resulting in elevated phosphate concentration and deposition of calcified deposits in cutaneous and subcutaneous tissues, as well as, occasionally, in visceral organs. The disease was found to result from mutations in at least 3 genes: GALNT3, encoding a glycosyltransferase termed ppGalNacT3, FGF23 encoding a potent phosphaturic protein, and KL encoding Klotho. Recent data showed that ppGalNacT3 mediates O-glycosylation of FGF23, thereby allowing for its secretion and possibly protecting it from proteolysis-mediated inactivation. Klotho was found to serve as a co-receptor for FGF23, thereby integrating the genetic data into a single physiological system. The elucidation of the molecular basis of HFTC shed new light upon the mechanisms regulating phosphate homeostasis, suggesting innovative therapeutic strategies for the management of Hyperphosphatemia in common acquired conditions such as chronic renal failure.
-
GALNT3, a gene associated with hyperphosphatemic familial tumoral calcinosis, is transcriptionally regulated by extracellular phosphate and modulates matrix metalloproteinase activity
Biochimica et biophysica acta, 2008Co-Authors: Ilana Chefetz, Kimitoshi Kohno, Hiroto Izumi, Jouni Uitto, Gabriele Richard, Eli SprecherAbstract:GALNT3 encodes UDP-N-acetyl-alpha-d-galactosamine: polypeptide N-acetylgalactosaminyl-transferarase 3 (ppGalNacT3), a glycosyltransferase which has been suggested to prevent proteolysis of FGF23, a potent phosphaturic protein. Accordingly, loss-of-function mutations in GALNT3 cause hyperphosphatemic familial tumoral calcinosis (HFTC), a rare autosomal recessive disorder manifesting with increased kidney reabsorption of phosphate, resulting in severe Hyperphosphatemia and widespread ectopic calcifications. Although these findings definitely attribute a role to ppGalNacT3 in the regulation of phosphate homeostasis, little is currently known about the factors regulating GALNT3 expression. In addition, the effect of decreased GALNT3 expression in peripheral tissues has not been explored so far. In the present study, we demonstrate that GALNT3 expression is under the regulation of a number of factors known to be associated with phosphate homeostasis, including inorganic phosphate itself, calcium and 1,25-dihydroxyvitamin D(3). In addition, we show that decreased GALNT3 expression in human skin fibroblasts leads to increased expression of FGF7 and of matrix metalloproteinases, which have been previously implicated in the pathogenesis of ectopic calcification. Thus, the present data suggest that ppGalNacT3 may play a role in peripheral tissues of potential relevance to the pathogenesis of disorders of phosphate metabolism.
-
identification of a recurrent mutation in galnt3 demonstrates that hyperostosis Hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders
Journal of Molecular Medicine, 2005Co-Authors: Yaacov Frishberg, Gabriele Richard, Orit Topaz, Reuven Bergman, Doron M Behar, Drora Fisher, Derek Gordon, Eli SprecherAbstract:Hyperphosphatemia-hyperostosis syndrome (HHS) is a rare autosomal recessive metabolic disorder characterized by elevated serum phosphate levels and repeated attacks of acute, painful swellings of the long bones with radiological evidence of periosteal reaction and cortical hyperostosis. HHS shares several clinical and metabolic features with hyperphosphatemic familial tumoral calcinosis (HFTC), which is caused by mutations in GALNT3 encoding a glycosyltransferase responsible for initiating O-glycosylation. To determine whether GALNT3 is involved in the pathogenesis of HHS we screened two unrelated Arab-Israeli HHS families for pathogenic mutations in this gene. All affected individuals harbored a homozygous splice site mutation (1524+1G-->A) in GALNT3. This mutation was previously described in a large Druze HFTC kindred and has been shown to alter GALNT3 expression and result in ppGalNAc-T3 deficiency. Genotype analysis of six microsatellite markers across the GALNT3 region on 2q24-q31 revealed that the HHS and HFTC families share a common haplotype spanning approximately 0.14 Mb. Our results demonstrate that HHS and HFTC are allelic disorders despite their phenotypic differences and suggest a common origin of the 1524+1G-->A mutation in the Middle East (founder effect). The heterogeneous phenotypic expression of the identified splice site mutation implies the existence of inherited or epigenetic modifying factors of importance in the regulation of ppGalNAc-T3 activity.
Cecilia M Giachelli - One of the best experts on this subject based on the ideXlab platform.
-
phosphate regulation of vascular smooth muscle cell calcification
Circulation Research, 2000Co-Authors: Shuichi Jono, Marc D Mckee, Charles E Murry, Atsushi Shioi, Yoshiki Nishizawa, Katsuhito Mori, Hirotoshi Morii, Cecilia M GiachelliAbstract:Abstract —Vascular calcification is a common finding in atherosclerosis and a serious problem in diabetic and uremic patients. Because of the correlation of Hyperphosphatemia and vascular calcification, the ability of extracellular inorganic phosphate levels to regulate human aortic smooth muscle cell (HSMC) culture mineralization in vitro was examined. HSMCs cultured in media containing normal physiological levels of inorganic phosphate (1.4 mmol/L) did not mineralize. In contrast, HSMCs cultured in media containing phosphate levels comparable to those seen in hyperphosphatemic individuals (>1.4 mmol/L) showed dose-dependent increases in mineral deposition. Mechanistic studies revealed that elevated phosphate treatment of HSMCs also enhanced the expression of the osteoblastic differentiation markers osteocalcin and Cbfa-1. The effects of elevated phosphate on HSMCs were mediated by a sodium-dependent phosphate cotransporter (NPC), as indicated by the ability of the specific NPC inhibitor phosphonoformic acid, to dose dependently inhibit phosphate-induced calcium deposition as well as osteocalcin and Cbfa-1 gene expression. With the use of polymerase chain reaction and Northern blot analyses, the NPC in HSMCs was identified as Pit-1 (Glvr-1), a member of the novel type III NPCs. These data suggest that elevated phosphate may directly stimulate HSMCs to undergo phenotypic changes that predispose to calcification and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. The full text of this article is available at http://www.circresaha.org.
Yogesh N.v. Reddy - One of the best experts on this subject based on the ideXlab platform.
-
Optimal management of Hyperphosphatemia in end-stage renal disease: an Indian perspective
International journal of nephrology and renovascular disease, 2014Co-Authors: Georgi Abraham, Varun Sundaram, P. Nagarajan, Yogesh N.v. ReddyAbstract:There has been an exponential increase in the incidence of diabetes and hypertension in India in the last few decades, with a proportional increase in chronic kidney disease (CKD). Preventive health care and maintenance of asymptomatic chronic disease such as CKD are often neglected by patients until they become symptomatic with fluid retention and uremia. Management of Hyperphosphatemia in CKD remains one of the challenges of nephrology in India for this reason, as it is almost completely asymptomatic but contributes to renal osteodystrophy, metastatic vascular calcification, and acceleration of cardiovascular disease. Lack of understanding of the dangers of asymptomatic Hyperphosphatemia, the huge pill burden of phosphate binders, difficulty with dietary and dialysis compliance, and most importantly, the added expense of the drugs places additional road blocks in the treatment of Hyperphosphatemia at a population level in developing countries like India. In this review we seek to address the contribution of Hyperphosphatemia to adverse outcomes and discuss economic, cultural, and societal factors unique to the management of phosphate levels in Indian patients with advanced CKD.
Shuichi Jono - One of the best experts on this subject based on the ideXlab platform.
-
Hyperphosphatemia and vascular calcification in end stage renal disease
Journal of Renal Nutrition, 2005Co-Authors: Yoshiki Nishizawa, Shuichi Jono, Eiji Ishimura, Atsushi ShioiAbstract:Vascular calcification is a common finding in atherosclerosis and a serious problem in uremic patients. Because of the correlation of Hyperphosphatemia and vascular calcification, the ability of extracellular inorganic phosphate levels to regulate human aortic smooth muscle cell (HSMC) culture mineralization in vitro was examined. HSMC cultured in media containing normal physiologic levels of inorganic phosphate (1.4 mM) did not mineralize. In contrast, HSMC cultured in media containing phosphate levels comparable with those seen in hyperphosphatemic individuals (>1.4 mM) showed dose-dependent increases in mineral deposition. Mechanistic studies showed that elevated phosphate treatment of HSMC also enhanced the expression of the osteoblastic differentiation markers osteocalcin and osf2/Cbfa-1. The effects of elevated phosphate on HSMC were mediated by a sodium-dependent phosphate cotransporter (NPC) as indicated by the ability of the specific NPC inhibitor phosphonoformic acid to dose-dependently inhibit phosphate-induced calcium deposition as well as osteocalcin and Cbfa-1 gene expression. The NPC in HSMC was identified as Pit-1, a member of the novel type III NPCs. These data suggest that elevated phosphate may directly stimulate HSMC to undergo phenotypic changes that predispose to calcification and offers a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. Furthermore, we examined the factors affecting peripheral vascular calcification in 332 nondiabetic hemodialysis patients. There were 45 nondiabetic patients with vascular calcification. In multivariate logistic regression, the significant factors affecting vascular calcification were advanced age, longer duration of hemodialysis, increased phosphate concentrations, male gender, and lower predialysis diastolic pressure. Our findings suggest that an elevated phosphate level may directly stimulate HSMC to undergo phenotypic changes that predispose to calcification and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions.
-
phosphate regulation of vascular smooth muscle cell calcification
Circulation Research, 2000Co-Authors: Shuichi Jono, Marc D Mckee, Charles E Murry, Atsushi Shioi, Yoshiki Nishizawa, Katsuhito Mori, Hirotoshi Morii, Cecilia M GiachelliAbstract:Abstract —Vascular calcification is a common finding in atherosclerosis and a serious problem in diabetic and uremic patients. Because of the correlation of Hyperphosphatemia and vascular calcification, the ability of extracellular inorganic phosphate levels to regulate human aortic smooth muscle cell (HSMC) culture mineralization in vitro was examined. HSMCs cultured in media containing normal physiological levels of inorganic phosphate (1.4 mmol/L) did not mineralize. In contrast, HSMCs cultured in media containing phosphate levels comparable to those seen in hyperphosphatemic individuals (>1.4 mmol/L) showed dose-dependent increases in mineral deposition. Mechanistic studies revealed that elevated phosphate treatment of HSMCs also enhanced the expression of the osteoblastic differentiation markers osteocalcin and Cbfa-1. The effects of elevated phosphate on HSMCs were mediated by a sodium-dependent phosphate cotransporter (NPC), as indicated by the ability of the specific NPC inhibitor phosphonoformic acid, to dose dependently inhibit phosphate-induced calcium deposition as well as osteocalcin and Cbfa-1 gene expression. With the use of polymerase chain reaction and Northern blot analyses, the NPC in HSMCs was identified as Pit-1 (Glvr-1), a member of the novel type III NPCs. These data suggest that elevated phosphate may directly stimulate HSMCs to undergo phenotypic changes that predispose to calcification and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. The full text of this article is available at http://www.circresaha.org.
Francisco Llach - One of the best experts on this subject based on the ideXlab platform.
-
Hyperphosphatemia in end-stage renal disease patients: pathophysiological consequences.
Kidney International, 1999Co-Authors: Francisco LlachAbstract:Hyperphosphatemia in end-stage renal disease patients: Pathophysiological consequences. A study of 6407 end-stage renal disease (ESRD) patients has shown that Hyperphosphatemia is increasingly important as a risk for mortality. Half of the patients showed serum phosphorus levels of over 6.0 mg/dl; at the same time, an elevated calcium × phosphorus product indicated increased risk of mortality. These observations lead to questions regarding the mechanisms at work in both the observed phenomena and the way in which they affect mortality. To answer these questions, an understanding of the pathophysiological consequences of Hyperphosphatemia is necessary.
-
Methods of controlling Hyperphosphatemia in patients with chronic renal failure.
Current opinion in nephrology and hypertension, 1993Co-Authors: Francisco Llach, Bijan NikakhtarAbstract:The problem of Hyperphosphatemia in patients with chronic renal failure is reviewed. The importance of high plasma phosphorus levels in the pathogenesis of hyperparathyroidism is concisely discussed. Basic concepts about phosphorus metabolism in normal persons and in patients with chronic renal failure are outlined. This is followed by a detailed discussion of the various therapeutic methods to control Hyperphosphatemia. Dietary restriction, dialysance of phosphorus, and the use of the currently available phosphorus binders are comprehensively discussed. Finally, the various clinical situations associated with failure to control Hyperphosphatemia are reviewed.