Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020438 (hypercalciuria)
 2,502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proper serum phosphate concentrations are maintained by a complex and poorly understood process. Identification of genes responsible for inherited disorders involving disturbances in phosphate homeostasis may provide insight into the pathways that regulate phosphate balance. Several hereditary disorders of isolated phosphate wasting have been described, including X-linked hypophosphataemic rickets (XLH), hypophosphataemic bone disease (HBD), hereditary hypophosphataemic rickets with hypercalciuria (HHRH) and autosomal dominant hypophosphataemic rickets (ADHR). Inactivating mutations of the gene PHEX, encoding a member of the neutral endopeptidase family of proteins, are responsible for XLH (refs 6,7). ADHR (MIM 193100) is characterized by low serum phosphorus concentrations, rickets, osteomalacia, lower extremity deformities, short stature, bone pain and dental abscesses. Here we describe a positional cloning approach used to identify the ADHR gene which included the annotation of 37 genes within 4 Mb of genomic sequence. We identified missense mutations in a gene encoding a new member of the fibroblast growth factor (FGF) family, FGF23. These mutations in patients with ADHR represent the first mutations found in a human FGF gene.
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PMID:Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. 1106 77

X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets, hereditary hypophosphatemic rickets with hypercalciuria, and tumor-induced osteomalacia share clinical and biochemical features, and are collectively referred to as hypophosphatemic rickets (HR). Recently, the molecular bases of HR were elucidated. A review of medical records and mutational analyses of the PHEX and FGF23 genes were performed on 17 unrelated Korean children with HR. The male-to-female ratio was 3:14, and 5 patients were familial. Initial laboratory tests revealed typical features of HR. Seven different PHEX mutations were detected in 8 patients: 2 missense mutations, 2 nonsense mutations, and 3 short deletions. No functional FGF23 mutation was detected in any patient. Patients with the PHEX mutation tended to have more severe skeletal disease than those without. Of the patients with this mutation, no genotype-phenotype correlation and no gene dosage effect were noted. Treatment with vitamin D and phosphate resulted in only a partial growth improvement in most cases, and was frequently complicated by hypercalciuria, hypercalcemia, nephrocalcinosis, or hyperparathyroidism. Renal glycosuria was detected in six cases and was associated with more severe skeletal disease. We conclude that current HR treatment is not fully safe or effective, and that close monitoring of treatment effectiveness and for complications should be performed during long-term treatment. No genotype-phenotype correlation in XLH was detected in this study, but a large-scaled study on this topic is warranted. The large proportion of patients with a normal genetic study suggests the possibility of other causative gene(s).
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PMID:A clinical and molecular genetic study of hypophosphatemic rickets in children. 1605 33

Hereditary hypophosphatemic rickets groups together X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR) and hereditary hypophosphatemic rickets with hypercalciuria (HHRH, autosomal recessive). Clinical and biological characteristics and treatment depend on specific etiology. Mutations causing hereditary hypophosphatemic rickets involve PHEX located on Xp11.22 for XLH and FGF-23 located on 12p13 for ADHR. The gene involved in HHRH remains unknown: candidates may encode proteins that modulate phosphate transporter expression or activity. Others forms of rickets must be ruled out: acquired hypophosphatemia due to oncogenic osteomalacia, X-linked recessive hypophosphatemic rickets or Dent's disease, and hereditary 1, 25-dihydroxyvitamin D-resistant rickets with a defect either in the 1-alpha-hydroxylase gene (pseudo-vitamin D deficiency rickets, PDDR) or in the vitamin D receptor (hereditary vitamin D-resistant rickets, HVDRR).
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PMID:[Hereditary hypophosphatemia in adults]. 1637 96

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.
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PMID:Phosphate transport: molecular basis, regulation and pathophysiology. 1727 Apr 30

The regulation of phosphate homeostasis remains incompletely understood. Most insights into the underlying mechanisms were established by defining the molecular basis of different inherited disorders that are characterized by an abnormal regulation of phosphate homeostasis. Using this approach, three novel regulators were previously identified, namely PHEX (a phosphate-regulating gene with homologies to endopeptidases on the X chromosome), fibroblast growth factor (FGF)-23 and UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). Other studies had revealed heterozygous mutations in the sodium phosphate co-transporter NaPi-IIa as the cause of hypophosphatemia associated with hypercalciuria and osteoporosis, and homozygous or compound heterozygous mutations in NaPi-IIc were shown to cause hereditary hypophosphatemic rickets with hypercalciuria. Recently, positional cloning approaches furthermore led to the identification of homozygous inactivating mutations in dentin matrix protein 1 (DMP1) as the cause of an autosomal recessive form of hypophosphatemia. Using different immunometric assays, intact and C-terminal FGF-23 levels were found to be elevated in patients with oncogenic osteomalacia, and the tumors responsible for this disease showed increased expression of FGF-23 mRNA. Intact and C-terminal FGF-23 levels are furthermore elevated in patients with X-linked hypophosphatemia. This disorder is caused by inactivating PHEX mutations suggesting that this endopeptidase is somehow, most likely indirectly, involved in the metabolism of intact FGF-23. FGF-23 levels were also found to be elevated in some patients with ARHP indicating that the lack of DMP1 up-regulates expression of this phosphaturic hormone. The concentration of C-terminal FGF-23, but not of intact FGF-23, is significantly elevated in two forms of tumoral calcinosis (TC). One form of TC is caused by homozygous inactivating GALNT3 mutations implying that the encoded enzyme, which is involved in the initiation of O-glycosylation, is important for preventing cleavage of FGF-23 into biologically inactive fragments. The second form of tumoral calcinosis is caused by different homozygous FGF-23 mutations that affect conserved serine residues that may undergo O-glycosylation by GALNT3; the lack of this post-translational modification leads to an abnormal processing of FGF-23 and increased secretion of C-terminal fragments. It remains unknown whether and how the different phosphate-regulating proteins interact with each other and it appears very likely that additional proteins are involved in this process. It also remains unclear whether the dramatically elevated FGF-23 levels in patients with different stages of chronic kidney disease affect bone metabolism, particularly the mineralization of newly formed osteoid.
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PMID:Novel regulators of phosphate homeostasis and bone metabolism. 1797 82

Phosphorous is essential for multiple cellular functions and constitutes an important mineral in bone. Hypophosphatemia in children leads to rickets resulting in abnormal growth and often skeletal deformities. Among various causes of low serum phosphorous are inherited disorders associated with increased urinary excretion of phosphate, including autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemia (XLH), autosomal recessive hypophosphatemia (ARHP), and hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Recent genetic analyses and subsequent biochemical and animal studies have revealed several novel molecules that appear to play key roles in the regulation of renal phosphate handling. These include a protein with abundant expression in bone, fibroblast growth factor 23 (FGF23), which has proven to be a circulating hormone that inhibits tubular reabsorption of phosphate in the kidney. Two other bone-specific proteins, PHEX and dentin matrix protein 1 (DMP1), appear to be necessary for limiting the expression of fibroblast growth factor 23, thereby allowing sufficient renal conservation of phosphate. This review focuses on the clinical, biochemical, and genetic features of inherited hypophosphatemic disorders, and presents the current understanding of hormonal and molecular mechanisms that govern phosphorous homeostasis.
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PMID:Inherited hypophosphatemic disorders in children and the evolving mechanisms of phosphate regulation. 1836 15

X-linked dominant hypophosphatemic rickets (XLH) is the most prevalent genetic form of hypophosphatemic rickets. Standard treatment of XLH patients includes long-term administration of phosphate and calcitriol. Treated patients usually respond well to the conventional therapy and demonstrate amelioration of rachitic symptoms and improved growth. However, long-term administration of phosphate and vitamin D preparations is sometimes complicated with nephrocalcinosis, secondary or tertiary hyperparathyroidism and arterial hypertension. We describe a patient with XLH, caused by a rare missense mutation of the PHEX gene. The patient, while under treatment with alphacalcidol and oral phosphate, developed hypercalciuria, nephrocalcinosis, secondary hyperparathyroidism and arterial hypertension. Cinacalcet was added to the therapeutic regimen and the long-term effects on calciotropic parameters and FGF23 levels are herein reported.
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PMID:Cinacalcet in hyperparathyroidism secondary to X-linked hypophosphatemic rickets: case report and brief literature review. 2068 26

Fibroblast growth factor 23 (FGF23) is part of a previously unrecognized hormonal bone-parathyroid-kidney axis, which is modulated by 1,25(OH)(2)-vitamin D (1,25(OH)(2)D), dietary and circulating phosphate and possibly PTH. FGF23 was discovered as the humoral factor in tumors that causes hypophosphatemia and osteomalacia and through the identification of a mutant form of FGF23 that leads to autosomal dominant hypophosphatemic rickets (ADHR), a rare genetic disorder. FGF23 appears to be mainly secreted by osteocytes where its expression is up-regulated by 1,25(OH)(2)D and probably by increased serum phosphate levels. Its synthesis and secretion is reduced through yet unknown mechanisms that involve the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX), dentin matrix protein 1 (DMP1) and ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). Consequently, loss-of-function mutations in these genes underlie hypophosphatemic disorders that are either X-linked or autosomal recessive. Impaired O-glycosylation of FGF23 due to the lack of UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyl-transferase 3 (GALNT3) or due to certain homozygous FGF23 mutations results in reduced secretion of intact FGF23 and leads to familial hyperphosphatemic tumoral calcinosis. FGF23 acts through FGF-receptors and the coreceptor Klotho to reduce 1,25(OH)(2)D synthesis in the kidney and probably the synthesis of parathyroid hormone (PTH) by the parathyroid glands. It furthermore synergizes with PTH to increase renal phosphate excretion by reducing expression of the sodium-phosphate cotransporters NaPi-IIa and NaPi-IIc in the proximal tubules. Loss-of-function mutations in these two transporters lead to autosomal recessive Fanconi syndrome or to hereditary hypophosphatemic rickets with hypercalciuria, respectively.
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PMID:FGF23 and syndromes of abnormal renal phosphate handling. 2239 61