The Experts below are selected from a list of 2085 Experts worldwide ranked by ideXlab platform
Shoji Ichikawa - One of the best experts on this subject based on the ideXlab platform.
-
a mutation in the dmp1 gene alters phosphate responsiveness in mice
Endocrinology, 2017Co-Authors: Shoji Ichikawa, Rita Gerardoriley, Dena Acton, Amie K Mcqueen, Isabel E Strobel, Phillip C Witcher, Jian Q Feng, Michael J EconsAbstract:Mutations in the dentin matrix protein 1 (DMP1) gene cause autosomal recessive hypophosphatemic rickets (ARHR). Hypophosphatemia in ARHR results from increased circulating levels of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Similarly, elevated FGF23, caused by mutations in the PHEX gene, is responsible for the hypophosphatemia in X-linked hypophosphatemic rickets (XLH). Previously, we demonstrated that a Phex mutation in mice creates a lower set point for extracellular phosphate, where an increment in phosphorus further stimulates Fgf23 production to maintain low serum phosphorus levels. To test the presence of the similar set point defect in ARHR, we generated 4- and 12-week-old Dmp1/GALNT3 double knockout mice and controls, including Dmp1 knockout mice (a murine model of ARHR), GALNT3 knockout mice (a murine model of familial tumoral calcinosis), and phenotypically normal double heterozygous mice. GALNT3 knockout mice had increased proteolytic cleavage of Fgf23, leading to low circulating intact Fgf23 levels with consequent hyperphosphatemia. In contrast, Dmp1 knockout mice had little Fgf23 cleavage and increased femoral Fgf23 expression, resulting in hypophosphatemia and low femoral bone mineral density (BMD). However, introduction of the GALNT3 null allele to Dmp1 knockout mice resulted in a significant increase in serum phosphorus and normalization of BMD. This increased serum phosphorus was accompanied by markedly elevated Fgf23 expression and circulating Fgf23 levels, an attempt to reduce serum phosphorus in the face of improving phosphorus levels. These data indicate that a Dmp1 mutation creates a lower set point for extracellular phosphate and maintains it through the regulation of Fgf23 cleavage and expression.
-
High Dietary Phosphate Intake Induces Development of Ectopic Calcifications in a Murine Model of Familial Tumoral Calcinosis
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2014Co-Authors: Shoji Ichikawa, Amie K. Gray, Leah R. Padgett, Austin M. Reilly, Tyler R UnsickerAbstract:Familial tumoral calcinosis is characterized by ectopic calcifications due to persistent hyperphosphatemia. The most common genetic cause of the disease is mutations in GALNT3, encoding a glycosyltransferase involved in a posttranslational modification of fibroblast growth factor 23 (FGF23). The GALNT3 knockout mouse we developed was hyperphosphatemic due to low intact Fgf23 levels, but did not develop any apparent calcifications on a standard rodent diet. We therefore tested the hypothesis that a further challenge with a high phosphate diet could induce ectopic calcifications in GALNT3 knockout mice. Mice were fed either normal (0.6%) or high (1.65%) phosphate diet for 20 weeks beginning from weaning at 3 weeks. The high phosphate diet did not affect serum phosphorus concentration. However, regardless of the dietary phosphate contents, serum phosphorus levels were consistently elevated in GALNT3 knockout mice. The mice on the high phosphate diet had slightly low serum calcium, but significantly high alkaline phosphatase, parathyroid hormone (PTH), and calcium in the kidney. Although none of GALNT3 knockout mice on the normal phosphate diet developed calcifications, calcifications appeared in approximately one-half of the mice on the high phosphate diet by 12 weeks. Calcified masses were most often found around the neck and on the back and as large as 9.9 mm in length. These data indicate that dietary phosphate load has major impact on the development of ectopic calcifications in tumoral calcinosis. © 2014 American Society for Bone and Mineral Research.
-
Genetic Rescue of Glycosylation-deficient Fgf23 in the GALNT3 Knockout Mouse
Endocrinology, 2014Co-Authors: Shoji Ichikawa, Amie K. Gray, Leah R. Padgett, Matthew R. Allen, Erica L. Clinkenbeard, Nicole M. Sarpa, Kenneth E. White, Michael J EconsAbstract:Fibroblast growth factor 23 (FGF23) is a hormone that inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D biosynthesis. The FGF23 subtilisin-like proprotein convertase recognition sequence (176RHTR179↓) is protected by O-glycosylation through ppGalNAc-T3 (GALNT3) activity. Thus, inactivating GALNT3 mutations render FGF23 susceptible to proteolysis, thereby reducing circulating intact hormone levels and leading to hyperphosphatemic familial tumoral calcinosis. To further delineate the role of glycosylation in the Fgf23 function, we generated an inducible FGF23 transgenic mouse expressing human mutant FGF23 (R176Q and R179Q) found in patients with autosomal dominant hypophosphatemic rickets (ADHR) and bred this animal to GALNT3 knockout mice, a model of familial tumoral calcinosis. Due to the low intact Fgf23 level, GALNT3 knockout mice with wild-type Fgf23 alleles were hyperphosphatemic. In contrast, carriers of the mutant FGF23 transgene, regardless of GALNT3 mutation status, had significantly higher serum intact FGF23, resulting in severe hypophosphatemia. Importantly, serum phosphorus and FGF23 were comparable between transgenic mice with or without normal GALNT3 alleles. To determine whether the presence of the ADHR mutation could improve biochemical and skeletal abnormalities in GALNT3-null mice, these mice were also mated to Fgf23 knock-in mice, carrying heterozygous or homozygous R176Q ADHR Fgf23 mutations. The knock-in mice with functional GALNT3 had normal Fgf23 but were slightly hypophosphatemic. The stabilized Fgf23 ADHR allele reversed the GALNT3-null phenotype and normalized total Fgf23, serum phosphorus, and bone Fgf23 mRNA. However, the skeletal phenotype was unaffected. In summary, these data demonstrate that O-glycosylation by ppGaINAc-T3 is only necessary for proper secretion of intact Fgf23 and, once secreted, does not affect Fgf23 function. Furthermore, the more stable Fgf23 ADHR mutant protein could normalize serum phosphorus in GALNT3 knockout mice.
-
Nicotinamide treatment in a murine model of familial tumoral calcinosis reduces serum Fgf23 and raises heart calcium
Bone, 2014Co-Authors: Austin M. Reilly, Amie K. Gray, Sharon M. Moe, Shoji IchikawaAbstract:Abstract Mutations in the GALNT3 gene result in familial tumoral calcinosis, characterized by persistent hyperphosphatemia and ectopic calcific masses in soft tissues. Since calcific masses often recur after surgical removal, a more permanent solution to the problem is required. Nicotinamide is reported to lower serum phosphate by decreasing sodium-dependent phosphate co-transporters in the gut and kidney. However, its effectiveness in tumoral calcinosis remains unknown. In this study, we investigated nicotinamide as a potential therapy for tumoral calcinosis, using a murine model of the disease—GALNT3 knockout mice. Initially, five different doses of nicotinamide were given to normal heterozygous mice intraperitoneally or orally. Treatment had no effect on serum phosphate levels, but serum levels of a phosphaturic hormone, fibroblast growth factor 23 (Fgf23), decreased in a dose-dependent manner. Subsequently, high-dose nicotinamide (40 mM) was tested in GALNT3 knockout mice fed a high phosphate diet. The radiographic data pre- and post-treatment showed that nicotinamide did not reverse the calcification. However, the treatment retarded calcification growth after 4 weeks, while in the untreated animals, calcifications increased in size. The therapy did not affect serum phosphate levels, but intact Fgf23 decreased in the treated mice. The treated mice also had increased calcium in the heart. In summary, nicotinamide did not alter serum phosphate levels, likely due to compensatory decrease in Fgf23 to counteract the phosphate lowering effect of nicotinamide. Although increased calcium accumulation in the heart is a concern, the therapy appears to slow down the progression of ectopic calcifications.
-
The phosphate-lowering effect of nicotinamide is offset by reduced Fgf23 levels in a murine model of familial tumoral calcinosis
Seminars in Arthritis and Rheumatism, 2013Co-Authors: Shoji Ichikawa, Austin M. ReillyAbstract:Familial tumoral calcinosis is caused by mutations in the GALNT3 gene. Lack of GalNAc transferase 3, encoded by GALNT3, destabilizes FGF23, a key hormone that suppresses phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis in the kidney. The destabilized FGF23 is more susceptible to proteolytic cleavage, thereby reducing the secretion of biologically active intact FGF23. Persistent hyperphosphatemia due to decreased FGF23 concentrations leads to often large, ectopic calcific masses in soft tissues, which are usually removed surgically. However, the calcific masses often recur, requiring a more permanent solution to the problem. Nicotinamide is reported to lower serum phosphate by decreasing type IIb sodium-dependent phosphate cotransporter in the gut. This effect of nicotinamide has promoted its use in treatment of limited cases of tumoral calcinosis, though its effectiveness remains largely unclear. Therefore, we investigated nicotinamide as a potential therapy for tumoral calcinosis, using a murine model of the disease – GALNT3 knockout mice. Initially, nicotinamide (doses 0, 2.5, 5, 7.5, and 10 mmol/kg/day) was given to normal mice for 2 weeks. Treatment had no effect on serum phosphate levels; however, Fgf23 was decreased in a dose-dependent manner. Subsequently, high-dose nicotinamide (10 mmol/kg/day) was tested for 4 weeks in GALNT3 knockout mice on a high-phosphate diet. The radiographic data pretreatment and posttreatments showed that the treatment did not eliminate the calcification, but retarded its growth, while in the untreated mice, calcifications increased in size. The therapy did not change serum phosphate levels despite moderately increased phosphate excretion, likely due to decreased serum intact Fgf23 levels. Quantification of calcium and phosphate contents in hearts and kidneys revealed that the treated mice had significantly high calcium in the heart. In summary, nicotinamide did not alter serum phosphate levels because the phosphate-lowering effect of nicotinamide was diminished by reduction in intact Fgf23 concentrations. The increased calcium in the heart suggests that nicotinamide therapy may also have an adverse effect.
Michael J Econs - One of the best experts on this subject based on the ideXlab platform.
-
a mutation in the dmp1 gene alters phosphate responsiveness in mice
Endocrinology, 2017Co-Authors: Shoji Ichikawa, Rita Gerardoriley, Dena Acton, Amie K Mcqueen, Isabel E Strobel, Phillip C Witcher, Jian Q Feng, Michael J EconsAbstract:Mutations in the dentin matrix protein 1 (DMP1) gene cause autosomal recessive hypophosphatemic rickets (ARHR). Hypophosphatemia in ARHR results from increased circulating levels of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Similarly, elevated FGF23, caused by mutations in the PHEX gene, is responsible for the hypophosphatemia in X-linked hypophosphatemic rickets (XLH). Previously, we demonstrated that a Phex mutation in mice creates a lower set point for extracellular phosphate, where an increment in phosphorus further stimulates Fgf23 production to maintain low serum phosphorus levels. To test the presence of the similar set point defect in ARHR, we generated 4- and 12-week-old Dmp1/GALNT3 double knockout mice and controls, including Dmp1 knockout mice (a murine model of ARHR), GALNT3 knockout mice (a murine model of familial tumoral calcinosis), and phenotypically normal double heterozygous mice. GALNT3 knockout mice had increased proteolytic cleavage of Fgf23, leading to low circulating intact Fgf23 levels with consequent hyperphosphatemia. In contrast, Dmp1 knockout mice had little Fgf23 cleavage and increased femoral Fgf23 expression, resulting in hypophosphatemia and low femoral bone mineral density (BMD). However, introduction of the GALNT3 null allele to Dmp1 knockout mice resulted in a significant increase in serum phosphorus and normalization of BMD. This increased serum phosphorus was accompanied by markedly elevated Fgf23 expression and circulating Fgf23 levels, an attempt to reduce serum phosphorus in the face of improving phosphorus levels. These data indicate that a Dmp1 mutation creates a lower set point for extracellular phosphate and maintains it through the regulation of Fgf23 cleavage and expression.
-
Genetic Rescue of Glycosylation-deficient Fgf23 in the GALNT3 Knockout Mouse
Endocrinology, 2014Co-Authors: Shoji Ichikawa, Amie K. Gray, Leah R. Padgett, Matthew R. Allen, Erica L. Clinkenbeard, Nicole M. Sarpa, Kenneth E. White, Michael J EconsAbstract:Fibroblast growth factor 23 (FGF23) is a hormone that inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D biosynthesis. The FGF23 subtilisin-like proprotein convertase recognition sequence (176RHTR179↓) is protected by O-glycosylation through ppGalNAc-T3 (GALNT3) activity. Thus, inactivating GALNT3 mutations render FGF23 susceptible to proteolysis, thereby reducing circulating intact hormone levels and leading to hyperphosphatemic familial tumoral calcinosis. To further delineate the role of glycosylation in the Fgf23 function, we generated an inducible FGF23 transgenic mouse expressing human mutant FGF23 (R176Q and R179Q) found in patients with autosomal dominant hypophosphatemic rickets (ADHR) and bred this animal to GALNT3 knockout mice, a model of familial tumoral calcinosis. Due to the low intact Fgf23 level, GALNT3 knockout mice with wild-type Fgf23 alleles were hyperphosphatemic. In contrast, carriers of the mutant FGF23 transgene, regardless of GALNT3 mutation status, had significantly higher serum intact FGF23, resulting in severe hypophosphatemia. Importantly, serum phosphorus and FGF23 were comparable between transgenic mice with or without normal GALNT3 alleles. To determine whether the presence of the ADHR mutation could improve biochemical and skeletal abnormalities in GALNT3-null mice, these mice were also mated to Fgf23 knock-in mice, carrying heterozygous or homozygous R176Q ADHR Fgf23 mutations. The knock-in mice with functional GALNT3 had normal Fgf23 but were slightly hypophosphatemic. The stabilized Fgf23 ADHR allele reversed the GALNT3-null phenotype and normalized total Fgf23, serum phosphorus, and bone Fgf23 mRNA. However, the skeletal phenotype was unaffected. In summary, these data demonstrate that O-glycosylation by ppGaINAc-T3 is only necessary for proper secretion of intact Fgf23 and, once secreted, does not affect Fgf23 function. Furthermore, the more stable Fgf23 ADHR mutant protein could normalize serum phosphorus in GALNT3 knockout mice.
-
a phex mutation in a murine model of x linked hypophosphatemia alters phosphate responsiveness of bone cells
Journal of Bone and Mineral Research, 2012Co-Authors: Shoji Ichikawa, Amie K. Gray, Michael J. Econs, Anthony M Austin, Shoji Ichikawa, Michael J EconsAbstract:Mutations in the PHEX gene cause X-linked hypophosphatemia (XLH). Hypophosphatemia in XLH results from increased circulating levels of a phosphaturic hormone, fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D (calcitriol) synthesis. The current standard therapy for XLH—high-dose phosphate and calcitriol—further increases FGF23 concentrations, suggesting that patients with XLH may have an altered response to extracellular phosphate. To test for the presence of abnormal phosphate responsiveness, we compared serum biochemistries and femoral Fgf23 mRNA expression between wild-type mice, murine models of XLH (PhexK496X) and hyperphosphatemic tumoral calcinosis (GALNT3−/−), and GALNT3/Phex double-mutant mice. Phex mutant mice had not only increased Fgf23 expression but also reduced proteolytic cleavage of intact Fgf23 protein, resulting in markedly elevated intact Fgf23 levels and consequent hypophosphatemia. In contrast, despite markedly increased Fgf23 expression, GALNT3 knockout mice had significantly high proteolytic cleavage of Fgf23 protein, leading to low intact Fgf23 concentrations and hyperphosphatemia. GALNT3/Phex double-mutant mice had an intermediate biochemical phenotype between wild-type and Phex mutant mice, including slightly elevated intact Fgf23 concentrations with milder hypophosphatemia. Despite the hypophosphatemia, double-mutant mice attempted to reduce serum phosphate back to the level of Phex mutant mice by upregulating Fgf23 expression as much as 24-fold higher than Phex mutant mice. These data suggest that Phex mutations alter the responsiveness of bone cells to extracellular phosphate concentrations and may create a lower set point for “normal” phosphate levels. © 2012 American Society for Bone and Mineral Research
-
A Phex mutation in a murine model of X-linked hypophosphatemia alters phosphate responsiveness of bone cells.
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2012Co-Authors: Shoji Ichikawa, Amie K. Gray, Anthony M Austin, Michael J EconsAbstract:Mutations in the PHEX gene cause X-linked hypophosphatemia (XLH). Hypophosphatemia in XLH results from increased circulating levels of a phosphaturic hormone, fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D (calcitriol) synthesis. The current standard therapy for XLH--high-dose phosphate and calcitriol--further increases FGF23 concentrations, suggesting that patients with XLH may have an altered response to extracellular phosphate. To test for the presence of abnormal phosphate responsiveness, we compared serum biochemistries and femoral Fgf23 mRNA expression between wild-type mice, murine models of XLH (Phex(K496X)) and hyperphosphatemic tumoral calcinosis (GALNT3(-/-)), and GALNT3/Phex double-mutant mice. Phex mutant mice had not only increased Fgf23 expression but also reduced proteolytic cleavage of intact Fgf23 protein, resulting in markedly elevated intact Fgf23 levels and consequent hypophosphatemia. In contrast, despite markedly increased Fgf23 expression, GALNT3 knockout mice had significantly high proteolytic cleavage of Fgf23 protein, leading to low intact Fgf23 concentrations and hyperphosphatemia. GALNT3/Phex double-mutant mice had an intermediate biochemical phenotype between wild-type and Phex mutant mice, including slightly elevated intact Fgf23 concentrations with milder hypophosphatemia. Despite the hypophosphatemia, double-mutant mice attempted to reduce serum phosphate back to the level of Phex mutant mice by upregulating Fgf23 expression as much as 24-fold higher than Phex mutant mice. These data suggest that Phex mutations alter the responsiveness of bone cells to extracellular phosphate concentrations and may create a lower set point for "normal" phosphate levels.
-
Dietary phosphate restriction normalizes biochemical and skeletal abnormalities in a murine model of tumoral calcinosis
Endocrinology, 2011Co-Authors: Shoji Ichikawa, Amie K. Gray, Anthony M Austin, Matthew R. Allen, Michael J EconsAbstract:Mutations in the GALNT3 gene cause tumoral calcinosis characterized by ectopic calcifications due to persistent hyperphosphatemia. We recently developed GALNT3 knockout mice in a mixed background, which had hyperphosphatemia with increased bone mineral density (BMD) and infertility in males. To test the effect of dietary phosphate intake on their phenotype, GALNT3 knockout mice were generated in the C57BL/6J strain and fed various phosphate diets: 0.1% (low), 0.3% (low normal), 0.6% (normal), and 1.65% (high). Sera were analyzed for calcium, phosphorus, alkaline phosphatase, creatinine, blood urine nitrogen, 1,25-dihydroxyvitamin D, osteocalcin, tartrate-resistant acid phosphatase 5b, and fibroblast growth factor 23 (Fgf23). Femurs were evaluated by dual-energy x-ray absorptiometry, dynamic histomorphometry, and/or microcomputed tomography. GALNT3 knockout mice in C57BL/6J had the same biochemical phenotype observed in our previous study: hyperphosphatemia, inappropriately normal 1,25-dihydroxyvitamin D level, decreased alkaline phosphatase activity, and low intact Fgf23 concentration but high Fgf23 fragments. Skeletal analyses of their femurs revealed significantly high BMD with increased cortical bone area and trabecular bone volume. On all four phosphate diets, GALNT3 knockout mice had consistently higher phosphorus levels and lower alkaline phosphatase and intact Fgf23 concentrations than littermate controls. The low-phosphate diet normalized serum phosphorus, alkaline phosphatase, and areal BMD but failed to correct male infertility in GALNT3 knockout mice. The high-phosphate diet did not increase serum phosphorus concentration in either mutant or control mice due to a compensatory increase in circulating intact Fgf23 levels. In conclusion, dietary phosphate restriction normalizes biochemical and skeletal phenotypes of GALNT3 knockout mice and, thus, can be an effective therapy for tumoral calcinosis.
Erik A Imel - One of the best experts on this subject based on the ideXlab platform.
-
Hyperphosphatemic Familial Tumoral Calcinosis: Genetic Models of Deficient FGF23 Action
Current Osteoporosis Reports, 2015Co-Authors: Lisal J. Folsom, Erik A ImelAbstract:Hyperphosphatemic familial tumoral calcinosis (hFTC) is a rare disorder of phosphate metabolism defined by hyperphosphatemia and ectopic calcifications in various locations. To date, recessive mutations have been described in three genes involving phosphate metabolism: FGF23 , GALNT3 , and α-Klotho , all of which result in the phenotypic presentation of hFTC. These mutations result in either inadequate intact fibroblast growth factor-23 (FGF23) secretion ( FGF23 or GALNT3 ) or resistance to FGF23 activity at the fibroblast growth factor receptor/α-Klotho complex ( α-Klotho ). The biochemical consequence of limitations in FGF23 activity includes increased renal tubular reabsorption of phosphate, hyperphosphatemia, and increased production of 1,25-dihydroxyvitamin D. The resultant ectopic calcifications can be painful and debilitating. Medical treatments are targeted toward decreasing intestinal phosphate absorption or increasing phosphate excretion; however, results have been variable and generally limited. Treatments that would increase FGF23 levels or signaling would more appropriately target the genetic etiologies of this disease and perhaps be more effective.
-
hyperphosphatemic familial tumoral calcinosis fgf23 GALNT3 and αklotho
Best Practice & Research: Clinical Rheumatology, 2011Co-Authors: Emily G. Farrow, Erik A Imel, Kenneth E. WhiteAbstract:Familial tumoral calcinosis (TC) is a rare disorder distinguished by the development of ectopic and vascular calcified masses that occur in settings of hyperphosphatemia (hFTC) and normophosphatemia (nFTC). Serum phosphorus concentrations are relatively tightly controlled by interconnected endocrine activity at the level of the intestine, kidney, and skeleton. Discovering the molecular causes for heritable forms of hFTC has shed new light on the regulation of serum phosphate balance. This review will focus upon the genetic basis and clinical approaches for hFTC, due to genes that are related to the phosphaturic hormone fibroblast growth factor-23 ( FGF23 ). These include FGF23 itself, an FGF23-glycosylating enzyme ( GALNT3 ), and the FGF23 co-receptor α-Klotho (α KL ). Our understanding of the molecular basis of hFTC will, in the short term, aid in understanding normal phosphate balance, and in the future, provide potential insight into the design of novel therapeutic strategies for both rare and common disorders of phosphate metabolism.
-
clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations
American Journal of Medical Genetics Part A, 2010Co-Authors: Shoji Ichikawa, Anthony M Austin, Andrea H. Sorenson, Leah R. Padgett, Genevieve Baujat, Aksel Seyahi, Anastasia G Garoufali, Erik A Imel, Zagorka Pejin, Vicken TopouchianAbstract:The GALNT3 gene encodes GalNAc-T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial tumoral calcinosis or its variant, hyperostosis-hyperphosphatemia syndrome. Tumoral calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis-hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including tumoral calcinosis and/or hyperostosis-hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia, as well as inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)2D]. Three of the patients also had confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia due to low intact FGF23, but other clinical manifestations were variable. Therefore, tumoral calcinosis and hyperostosis-hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.
-
Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations.
American journal of medical genetics. Part A, 2010Co-Authors: Shoji Ichikawa, Anthony M Austin, Andrea H. Sorenson, Leah R. Padgett, Genevieve Baujat, Aksel Seyahi, Anastasia G Garoufali, Erik A Imel, Zagorka Pejin, Vicken TopouchianAbstract:The GALNT3 gene encodes GalNAc-T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial tumoral calcinosis or its variant, hyperostosis-hyperphosphatemia syndrome. Tumoral calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis-hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including tumoral calcinosis and/or hyperostosis-hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia. Three of the patients also had inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)(2)D] and confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia as a result of low intact FGF23, but other clinical manifestations were variable. Therefore, tumoral calcinosis and hyperostosis-hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.
-
Novel GALNT3 mutations causing hyperostosis-hyperphosphatemia syndrome result in low intact fibroblast growth factor 23 concentrations.
Journal of Clinical Endocrinology and Metabolism, 2007Co-Authors: Shoji Ichikawa, Andrea H. Sorenson, Erik A Imel, Vincent Guigonis, Mélanie Courouble, Sophie Heissat, John D Henley, Barbara Petit, Anne Lienhardt-roussie, Michael J EconsAbstract:CONTEXT: Hyperostosis-hyperphosphatemia syndrome (HHS) is a rare metabolic disorder characterized by hyperphosphatemia and localized hyperostosis. HHS is caused by mutations in GALNT3, which encodes UDP-N-acetyl-alpha-D-galactosamine:polypeptide N- acetylgalactosaminyltransferase 3. Familial tumoral calcinosis (TC), characterized by ectopic calcifications and hyperphosphatemia, is caused by mutations in the GALNT3 or fibroblast growth factor 23 (FGF23) genes. OBJECTIVE: Our objective was to identify mutations in FGF23 or GALNT3 and determine serum FGF23 levels in an HHS patient. DESIGN: Mutation detection in FGF23 and GALNT3 was performed by DNA sequencing, and serum FGF23 concentrations were measured by ELISA. PATIENTS OR OTHER PARTICIPANTS: A 5-year-old French boy with HHS and his family members participated. RESULTS: The patient presented with painful cortical lesions in his leg. Radiographs of the affected bone showed diaphyseal hyperostosis. The lesional tissue comprised trabeculae of immature, woven bone surrounded by fibrous tissue. Biochemistry revealed elevated phosphate, tubular maximum rate for phosphate reabsorption per deciliter of glomerular filtrate, and 1,25-dihydroxyvitamin D levels. The patient was a compound heterozygote for two novel GALNT3 mutations. His parents and brother were heterozygous for one of the mutations and had no biochemical abnormalities. Intact FGF23 level in the patient was low normal, whereas C-terminal FGF23 was elevated, a pattern similar to TC. CONCLUSION: The presence of GALNT3 mutations and elevated C-terminal, but low intact serum FGF23, levels in HHS resemble those seen in TC, suggesting that HHS and TC are different manifestations of the same disorder. The absence of biochemical abnormalities in the heterozygous individuals suggests that one normal allele is sufficient for secretion of intact FGF23.
Vicken Topouchian - One of the best experts on this subject based on the ideXlab platform.
-
clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations
American Journal of Medical Genetics Part A, 2010Co-Authors: Shoji Ichikawa, Anthony M Austin, Andrea H. Sorenson, Leah R. Padgett, Genevieve Baujat, Aksel Seyahi, Anastasia G Garoufali, Erik A Imel, Zagorka Pejin, Vicken TopouchianAbstract:The GALNT3 gene encodes GalNAc-T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial tumoral calcinosis or its variant, hyperostosis-hyperphosphatemia syndrome. Tumoral calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis-hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including tumoral calcinosis and/or hyperostosis-hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia, as well as inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)2D]. Three of the patients also had confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia due to low intact FGF23, but other clinical manifestations were variable. Therefore, tumoral calcinosis and hyperostosis-hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.
-
Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations.
American journal of medical genetics. Part A, 2010Co-Authors: Shoji Ichikawa, Anthony M Austin, Andrea H. Sorenson, Leah R. Padgett, Genevieve Baujat, Aksel Seyahi, Anastasia G Garoufali, Erik A Imel, Zagorka Pejin, Vicken TopouchianAbstract:The GALNT3 gene encodes GalNAc-T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial tumoral calcinosis or its variant, hyperostosis-hyperphosphatemia syndrome. Tumoral calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis-hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including tumoral calcinosis and/or hyperostosis-hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia. Three of the patients also had inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)(2)D] and confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia as a result of low intact FGF23, but other clinical manifestations were variable. Therefore, tumoral calcinosis and hyperostosis-hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.
Andrea H. Sorenson - One of the best experts on this subject based on the ideXlab platform.
-
clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations
American Journal of Medical Genetics Part A, 2010Co-Authors: Shoji Ichikawa, Anthony M Austin, Andrea H. Sorenson, Leah R. Padgett, Genevieve Baujat, Aksel Seyahi, Anastasia G Garoufali, Erik A Imel, Zagorka Pejin, Vicken TopouchianAbstract:The GALNT3 gene encodes GalNAc-T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial tumoral calcinosis or its variant, hyperostosis-hyperphosphatemia syndrome. Tumoral calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis-hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including tumoral calcinosis and/or hyperostosis-hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia, as well as inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)2D]. Three of the patients also had confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia due to low intact FGF23, but other clinical manifestations were variable. Therefore, tumoral calcinosis and hyperostosis-hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.
-
Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations.
American journal of medical genetics. Part A, 2010Co-Authors: Shoji Ichikawa, Anthony M Austin, Andrea H. Sorenson, Leah R. Padgett, Genevieve Baujat, Aksel Seyahi, Anastasia G Garoufali, Erik A Imel, Zagorka Pejin, Vicken TopouchianAbstract:The GALNT3 gene encodes GalNAc-T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial tumoral calcinosis or its variant, hyperostosis-hyperphosphatemia syndrome. Tumoral calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis-hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including tumoral calcinosis and/or hyperostosis-hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia. Three of the patients also had inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)(2)D] and confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia as a result of low intact FGF23, but other clinical manifestations were variable. Therefore, tumoral calcinosis and hyperostosis-hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.
-
Ablation of the GALNT3 Gene Leads to Low-Circulating Intact Fibroblast Growth Factor 23 (Fgf23) Concentrations and Hyperphosphatemia Despite Increased Fgf23 Expression
Endocrinology, 2009Co-Authors: Shoji Ichikawa, Anthony M Austin, Andrea H. Sorenson, Donald S. Mackenzie, Timothy A. Fritz, Akira Moh, Siu L. Hui, Michael J EconsAbstract:Familial tumoral calcinosis is characterized by ectopic calcifications and hyperphosphatemia. The disease is caused by inactivating mutations in fibroblast growth factor 23 (FGF23), Klotho (KL), and uridine diphosphate-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). In vitro studies indicate that GALNT3 O-glycosylates a phosphaturic hormone, FGF23, and prevents its proteolytic processing, thereby allowing secretion of intact FGF23. In this study we generated mice lacking the GALNT3 gene, which developed hyperphosphatemia without apparent calcifications. In response to hyperphosphatemia, GALNT3-deficient mice had markedly increased Fgf23 expression in bone. However, compared with wild-type and heterozygous littermates, homozygous mice had only about half of circulating intact Fgf23 levels and higher levels of C-terminal Fgf23 fragments in bone. GALNT3-deficient mice also exhibited an inappropriately normal 1,25-dihydroxyvitamin D level and decreased alkaline phosphatase activity. Furthermore, renal expression of sodium-phosphate cotransporters and Kl were elevated in GALNT3-deficient mice. Interestingly, there were sex-specific phenotypes; only GALNT3-deficient males showed growth retardation, infertility, and significantly increased bone mineral density. In summary, ablation of GALNT3 impaired secretion of intact Fgf23, leading to decreased circulating Fgf23 and hyperphosphatemia, despite increased Fgf23 expression. Our findings indicate that GALNT3-deficient mice have a biochemical phenotype of tumoral calcinosis and provide in vivo evidence that GALNT3 plays an essential role in proper secretion of Fgf23 in mice.
-
Novel GALNT3 mutations causing hyperostosis-hyperphosphatemia syndrome result in low intact fibroblast growth factor 23 concentrations.
Journal of Clinical Endocrinology and Metabolism, 2007Co-Authors: Shoji Ichikawa, Andrea H. Sorenson, Erik A Imel, Vincent Guigonis, Mélanie Courouble, Sophie Heissat, John D Henley, Barbara Petit, Anne Lienhardt-roussie, Michael J EconsAbstract:CONTEXT: Hyperostosis-hyperphosphatemia syndrome (HHS) is a rare metabolic disorder characterized by hyperphosphatemia and localized hyperostosis. HHS is caused by mutations in GALNT3, which encodes UDP-N-acetyl-alpha-D-galactosamine:polypeptide N- acetylgalactosaminyltransferase 3. Familial tumoral calcinosis (TC), characterized by ectopic calcifications and hyperphosphatemia, is caused by mutations in the GALNT3 or fibroblast growth factor 23 (FGF23) genes. OBJECTIVE: Our objective was to identify mutations in FGF23 or GALNT3 and determine serum FGF23 levels in an HHS patient. DESIGN: Mutation detection in FGF23 and GALNT3 was performed by DNA sequencing, and serum FGF23 concentrations were measured by ELISA. PATIENTS OR OTHER PARTICIPANTS: A 5-year-old French boy with HHS and his family members participated. RESULTS: The patient presented with painful cortical lesions in his leg. Radiographs of the affected bone showed diaphyseal hyperostosis. The lesional tissue comprised trabeculae of immature, woven bone surrounded by fibrous tissue. Biochemistry revealed elevated phosphate, tubular maximum rate for phosphate reabsorption per deciliter of glomerular filtrate, and 1,25-dihydroxyvitamin D levels. The patient was a compound heterozygote for two novel GALNT3 mutations. His parents and brother were heterozygous for one of the mutations and had no biochemical abnormalities. Intact FGF23 level in the patient was low normal, whereas C-terminal FGF23 was elevated, a pattern similar to TC. CONCLUSION: The presence of GALNT3 mutations and elevated C-terminal, but low intact serum FGF23, levels in HHS resemble those seen in TC, suggesting that HHS and TC are different manifestations of the same disorder. The absence of biochemical abnormalities in the heterozygous individuals suggests that one normal allele is sufficient for secretion of intact FGF23.
-
tumoral calcinosis presenting with eyelid calcifications due to novel missense mutations in the glycosyl transferase domain of the GALNT3 gene
The Journal of Clinical Endocrinology and Metabolism, 2006Co-Authors: Shoji Ichikawa, Andrea H. Sorenson, Erik A Imel, Rebecca Severe, Paul E Knudson, Gerald J Harris, Joseph L Shaker, Michael J EconsAbstract:Context: Familial tumoral calcinosis (TC) is a rare autosomal recessive disorder characterized by metastatic calcifications, often periarticular. Biochemical findings include hyperphosphatemia, high 1,25-dihydroxyvitamin D levels, and elevated tubular maximum for phosphate reabsorption per deciliter of glomerular filtrate (TmP/GFR). TC is caused by biallelic mutations of the genes encoding either fibroblast growth factor 23 (FGF23) or uridine diphosphate-N-acetyl-α-d-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc transferase 3 or GALNT3). Objective: The objective was to identify mutations in FGF23 or GALNT3 responsible for a mild TC phenotype by DNA sequencing and to determine serum FGF23 levels by ELISA. Patients or Other Participants: The subject was a 25-yr-old Caucasian woman with eyelid calcifications and biochemical features of TC. Results: Eyelid biopsy revealed superficial dermis calcifications. There was no history of metastatic calcifications, mineral homeostasis abnormali...
