Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypophosphatemia due to isolated renal phosphate wasting results from a heterogeneous group of disorders. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive form that is characterized by reduced renal phosphate reabsorption, hypophosphatemia, and rickets. It can be distinguished from other forms of hypophosphatemia by increased serum levels of 1,25-dihydroxyvitamin D resulting in hypercalciuria. Using SNP array genotyping, we mapped the disease locus in two consanguineous families to the end of the long arm of chromosome 9. The candidate region contained a sodium-phosphate cotransporter gene, SLC34A3, which has been shown to be expressed in proximal tubulus cells. Sequencing of this gene revealed disease-associated mutations in five families, including two frameshift and one splice-site mutation. Loss of function of the SLC34A3 protein presumably results in a primary renal tubular defect and is compatible with the HHRH phenotype. We also show that the phosphaturic factor FGF23 (fibroblast growth factor 23), which is increased in X-linked hypophosphatemic rickets and carries activating mutations in autosomal dominant hypophosphatemic rickets, is at normal or low-normal serum levels in the patients with HHRH, further supporting a primary renal defect. Identification of the gene mutated in a further form of hypophosphatemia adds to the understanding of phosphate homeostasis and may help to elucidate the interaction of the proteins involved in this pathway.
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PMID:Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. 1635 15

X-linked hypophosphatemic rickets (XLH) is an hereditary form of rickets due to isolated renal tubular phosphate wasting and impaired production of 1,25-dihydroxyvitamin D [1,25(OH)2D]. XLH is caused by mutations in the PHEX (phosphate regulating gene with homology to endopeptidases) gene, which is located on Xp22.1. The pathogenetic mechanisms by which mutations in the PHEX gene cause XLH are not completely known. Hypophosphatemia associated with disproportionate short stature and bone deformities of the lower limbs are the main findings in XLH patients. Some studies have shown that conventional treatment with vitamin D metabolites, such as 1,25(OH)2D3 or 1 alpha-hydroxyvitamin D3, combined with inorganic phosphate salts is able to improve serum phosphate concentrations and linear growth, as well as healing rickets. However, some patients may have poor beneficial effects by this therapy. On the other hand, some important treatment complications, such as hypervitaminosis D, nephrocalcinosis and secondary/tertiary hyperparathyroidism may occur during the current therapy. Despite conventional treatment, some patients may require surgical correction of bone deformities. In the light of the recent genetic advances the mechanisms that could be involved in the pathogenesis of XLH are discussed. Furthermore, the article reviews the effects of the medical treatment providing current recommendations for the management of XLH patients.
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PMID:Genetic advances, biochemical and clinical features and critical approach to treatment of patients with X-linked hypophosphatemic rickets. 1643 29

Fibrous dysplasia (FD) is a classic feature of McCune-Albright syndrome (MAS). Renal phosphate wasting commonly occurs in FD, contributing to the mineralization defect in FD lesions and in non-FD bones, potentially increasing bone deformity. The presence of phosphate wasting correlates with measures of FD disease activity. Hypophosphatemia and phosphate wasting in FD are accompanied by inappropriately normal or low 1,25-dihydroxyvitamin D3 concentrations, similar to X-linked hypophosphatemic rickets. Recently, fibroblast growth factor 23 (FGF23) has emerged as an important humoral factor regulating phosphate and vitamin D homeostasis. FGF23 inhibits renal tubular phosphate reabsorption and decreases 1,25-dihydroxyvitamin D3. Interestingly, FGF23 is produced by normal osteoblasts as well as the abnormal osteogenic precursors present in FD lesions. However, FD lesions likely produce FGF23 in an unregulated fashion. Elevated circulating FGF23 correlates with total body FD disease burden and the presence of phosphate wasting. MAS mutations increase immature osteoblast lineage cells causing FD, resulting in dysregulated FGF23 production and, hence, phosphate wasting.
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PMID:Fibrous dysplasia, phosphate wasting and fibroblast growth factor 23. 1798 92

X-linked dominant hypophosphatemia (XLH, OMIM307800), the most prevalent form of inherited rickets in humans, is a dominant disorder of phosphate homeostasis characterized by growth retardation, rachitic and osteomalacic bone disease, hypophosphatemia, and renal phosphate wasting. The gene responsible for XLH was identified by positional cloning and designated PHEX (formerly PEX) to depict a phosphate-regulating gene homologous with endopeptidases on the X chromosome. Recently, extensive mutation analysis of the PHEX gene has revealed a wide variety of gene defects in XLH. The ethnic distribution of the mutations is very widespread but only a few mutations in Chinese have been reported. To analyze the molecular basis in three unrelated Chinese families with XLH, we determined the nucleotide sequence of the PHEX gene and fibroblast growth factor 23 (FGF23) gene of affected members. The serum FGF23 concentrations of these patients with XLH were also measured. Three different novel mutations were observed in these three families: one deletion mutation c.264delG causing p.W88 X; one missense mutation c.1673C>G causing p.P558A; one nonsense mutation c.1809G>A causing p.W603 X. Serum concentration of FGF23 in XLH patients of these three families was significantly higher than normal. The results suggest that PHEX gene mutations were responsible for XLH in these patients and these mutations may contribute to a higher serum FGF23 level.
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PMID:Three novel mutations of the PHEX gene in three Chinese families with X-linked dominant hypophosphatemic rickets. 1804 99

Patients with X-linked hypophosphatemia (XLH) and the hyp-mouse, a model of XLH characterized by a deletion in the Phex gene, manifest hypophosphatemia, renal phosphate wasting, and rickets/osteomalacia. Cloning of the PHEX/Phex gene and mutations in affected patients and hyp-mice established that alterations in PHEX/Phex expression underlie XLH. Although PHEX/Phex expression occurs primarily in osteoblast lineage cells, transgenic Phex expression in hyp-mouse osteoblasts fails to rescue the phenotype, suggesting that Phex expression at other sites underlies XLH. To establish whether abnormal Phex in osteoblasts and/or osteocytes alone generates the HYP phenotype, we created mice with a global Phex knockout (Cre-PhexDeltaflox/y mice) and conditional osteocalcin-promoted (OC-promoted) Phex inactivation in osteoblasts and osteocytes (OC-Cre-PhexDeltaflox/y). Serum phosphorus levels in Cre-PhexDeltaflox/y, OC-Cre-PhexDeltaflox/y, and hyp-mice were lower than those in normal mice. Kidney cell membrane phosphate transport in Cre-PhexDeltaflox/y, OC-Cre-PhexDeltaflox/y, and hyp-mice was likewise reduced compared with that in normal mice. Abnormal renal phosphate transport in Cre-PhexDeltaflox/y and OC-Cre-PhexDeltaflox/y mice was associated with increased bone production and serum FGF-23 levels and decreased kidney membrane type IIa sodium phosphate cotransporter protein, as was the case in hyp-mice. In addition, Cre-PhexDeltaflox/y, OC-Cre-PhexDeltaflox/y, and hyp-mice manifested comparable osteomalacia. These data provide evidence that aberrant Phex function in osteoblasts and/or osteocytes alone is sufficient to underlie the hyp-mouse phenotype.
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PMID:Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia. 1817 53

X-linked hypophosphatemic rickets (XLH) is a dominantly inherited disorder characterized by renal phosphate wasting, aberrant vitamin D metabolism, and abnormal bone mineralization. XLH is caused by inactivating mutations in PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). In this study, we sequenced the PHEX gene in subjects from 26 kindreds who were clinically diagnosed with XLH. Sequencing revealed 18 different mutations, of which thirteen have not been reported previously. In addition to deletions, splice site mutations, and missense and nonsense mutations, a rare point mutation in the 3'-untranslated region (3'-UTR) was identified as a novel cause of XLH. In summary, we identified a wide spectrum of mutations in the PHEX gene. Our data, in accord with those of others, indicate that there is no single predominant PHEX mutation responsible for XLH.
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PMID:Mutational survey of the PHEX gene in patients with X-linked hypophosphatemic rickets. 1862 46

X-Linked hypophosphatemic rickets (HYP, XLH) is a disorder of phosphate homeostasis, characterized by renal phosphate wasting and hypophosphatemia, with normal to low 1,25-dihydroxy vitamin D3 serum levels. The purpose of our study was the detection of inactivating mutations in the PHEX gene, the key enzyme in the pathogenesis of XLH. The 16 patients, representing eight families, presented with suspected XLH from biochemical and clinical evidence. All 16 were referred for mutational analysis of the PHEX gene. We detected three novel disease-causing mutations, C59S, Q394X, and W602, for which a loss of function can be predicted. A G28S variation, found in two healthy probands, may be a rare polymorphism. Another mutation, A363 V, is localized on the same allele as the C59S mutation, thus its functional consequences cannot be proven. Furthermore, we detected a deletion of three nucleotides in exon 15 which resulted in the loss of amino acid threonine 535. Heterozygosity of this mutation in a male patient without any chromosomal aberrations suggests its presence as a mosaic. Novel large deletions were detected using multiplex ligation-dependent probe amplification (MLPA) analysis. Two of these deletions, loss of exon 22 alone or exons 21 and 22 together, may result in the translation of a C-terminal truncated protein. Two large deletions comprise exons 1-9 and exons 4-20, respectively, and presumably result in a nonfunctional protein. We conclude that molecular genetic analysis confirms the clinical diagnosis of XLH and should include sequence analysis as well as the search for large deletions, which is facilitated by MLPA.
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PMID:Mutational analysis of the PHEX gene: novel point mutations and detection of large deletions by MLPA in patients with X-linked hypophosphatemic rickets. 1951 79

Hereditary forms of renal phosphate wasting have been studied thoroughly in the past years. X-linked Hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and autosomal recessive hypophosphatemic rickets (ARHR) are known genetic disorders in which a disturbance of phosphatonins is a causative factor in the pathogenesis. We describe a comparable but yet undescribed disorder in a family in which a 53 year old man presented with a spontaneous fracture after suffering for years with severe fatigue and musculoskeletal pains. A low serum phosphate was discovered. The two subsequent generations of this family developed the same symptoms but at an earlier age. Almost all family members have been investigated and the majority appears to have low bone density and/or renal phosphate wasting and/or low serum phosphate. Remarkably no rickets was found. No elevation of FGF23 or mutations in the gene encoding FGF23 were found. We believe this is a new familial disorder of bone metabolism and phosphate homeostasis in which a disturbance of bone modulators may play a central role.
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PMID:A familial disorder with low bone density and renal phosphate wasting. 1971 54

FGF2 transgenic mice were developed in which type I collagen regulatory sequences drive the nuclear high molecular weight FGF2 isoforms in osteoblasts (TgHMW). The phenotype of TgHMW mice included dwarfism, decreased bone mineral density (BMD), osteomalacia, and decreased serum phosphate (P(i)). When TgHMW mice were fed a high P(i) diet, BMD was increased, and dwarfism was partially reversed. The TgHMW phenotype was similar to mice overexpressing FGF23. Serum FGF23 was increased in TgHMW mice. Fgf23 mRNA in bones and fibroblast growth factor receptors 1c and 3c and Klotho mRNAs in kidneys were increased in TgHMW mice, whereas the renal Na(+)/P(i) co-transporter Npt2a mRNA was decreased. Immunohistochemistry and Western blot analyses of TgHMW kidneys showed increased KLOTHO and decreased NPT2a protein. The results suggest that overexpression of HMW FGF2 increases FGF23/FGFR/KLOTHO signaling to down-regulate NPT2a, causing P(i) wasting, osteomalacia, and decreased BMD. We assessed whether HMW FGF2 expression was altered in the Hyp mouse, a mouse homolog of the human disease X-linked hypophosphatemic rickets/osteomalacia. Fgf2 mRNA was increased in bones, and Western blots showed increased FGF2 protein in nuclear fractions from osteoblasts of Hyp mice. In addition, immunohistochemistry demonstrated co-localization of FGF23 and HMW FGF2 protein in osteoblasts and osteocytes from Hyp mice. This study reveals a novel mechanism of regulation of the FGF23-P(i) homeostatic axis.
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PMID:Nuclear isoforms of fibroblast growth factor 2 are novel inducers of hypophosphatemia via modulation of FGF23 and KLOTHO. 1993 69

Hypophosphatemic rickets (HR) is a group of rare disorders caused by excessive renal phosphate wasting. The purpose of this cross-sectional study of 38 HR patients was to characterize the phenotype of adult HR patients. Moreover, skeletal and endodontic severity scores were defined to assess possible gender differences in disease severity in patients with genetically verified X-linked HR. Compared to normal reference data, i.e., z = 0, HR patients had significantly lower final height, with a mean difference in z-score of -1.9 (95% CI -2.4 to -1.4, P < 0.001). Compared to paired z-scores of final height, z-scores of leg length were significantly lower and those of sitting height were significantly higher (P < 0.001), resulting in disproportion as indicated by the significantly elevated sitting height ratio, mean difference in z-score of 2.6 (95% CI 2.1-3.1, P < 0.001). Z-scores of head circumference (median 1.4, range -0.4 to 5.5, P < 0.001) and z-scores of bone mineral density (BMD) of the lumbar spine (median 1.9, range -1.5 to 8.6, P < 0.001) were significantly elevated compared to normal reference data. The relative risk (RR) of fracture was reduced (RR = 0.34, 95% CI 0.20-0.57, P < 0.001). The skeletal severity score tended to be higher in males compared to females (P = 0.07), and no gender difference in endodontic severity was found. In conclusion, adult HR patients were characterized by short stature and were disproportioned. They had elevated BMD of the lumbar spine and a reduced risk of fractures. We found a tendency for males to be more severely affected than females.
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PMID:Phenotype presentation of hypophosphatemic rickets in adults. 2052 10


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