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01-09-2012 | Educational Review

Genetic disorders of phosphate regulation

Authors: Jyothsna Gattineni, Michel Baum

Published in: Pediatric Nephrology | Issue 9/2012

Abstract

Regulation of phosphate homeostasis is critical for many biological processes, and both hypophosphatemia and hyperphosphatemia can have adverse clinical consequences. Only a very small percentage (1%) of total body phosphate is present in the extracellular fluid, which is measured by routine laboratory assays and does not reflect total body phosphate stores. Phosphate is absorbed from the gastrointestinal tract via the transcellular route [sodium phosphate cotransporter 2b (NaPi2b)] and across the paracellular pathway. Approximately 85% of the filtered phosphate is reabsorbed from the kidney, predominantly in the proximal tubule, by NaPi2a and NaPi2c, which are present on the brush border membrane. Renal phosphate transport is tightly regulated. Dietary phosphate intake, parathyroid hormone (PTH), 1,25 (OH)2 vitamin D3, and fibroblast growth factor 23 (FGF23) are the principal regulators of phosphate reabsorption from the kidney. Recent advances in genetic techniques and animal models have identified many genetic disorders of phosphate homeostasis. Mutations in NaPi2a and NaPi2c; and hormonal dysregulation of PTH, FGF23, and Klotho, are primarily responsible for most genetic disorders of phosphate transport. The main focus of this educational review article is to discuss the genetic and clinical features of phosphate regulation disorders and provide understanding and treatment options.

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Amanzadeh J, Reilly RF (2006) Hypophosphatemia: an evidence-based approach to its clinical consequences and management. Nat Clin Pract Nephrol 2:136–148PubMedCrossRef

Naderi AS, Reilly RF (2010) Hereditary disorders of renal phosphate wasting. Nat Rev Nephrol 6:657–665CrossRef

Shaikh A, Berndt T, Kumar R (2008) Regulation of phosphate homeostasis by the phosphatonins and other novel mediators. Pediatr Nephrol 23:1203–1210PubMedCrossRef

Murer H, Forster I, Biber J (2004) The sodium phosphate cotransporter family SLC34. Pflugers Arch 447:763–767PubMedCrossRef

Danisi G, Bonjour JP, Straub RW (1980) Regulation of Na-dependent phosphate influx across the mucosal border of duodenum by 1,25-dihydroxycholecalciferol. Pflugers Arch 388:227–232PubMedCrossRef

Hattenhauer O, Traebert M, Murer H, Biber J (1999) Regulation of small intestinal Na-P(i) type IIb cotransporter by dietary phosphate intake. Am J Physiol 277:G756–G762PubMed

Hilfiker H, Hattenhauer O, Traebert M, Forster I, Murer H, Biber J (1998) Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine. Proc Natl Acad Sci U S A 95:14564–14569PubMedCrossRef

Virkki LV, Biber J, Murer H, Forster IC (2007) Phosphate transporters: a tale of two solute carrier families. Am J Physiol Renal Physiol 293:F643–F654PubMedCrossRef

Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS (1998) Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci U S A 95:5372–5377PubMedCrossRef

10.

Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, bu-Zahra H, Frappier D, Burkett K, Carpenter TO, Anderson D, Garabedian M, Sermet I, Fujiwara TM, Morgan K, Tenenhouse HS, Juppner H (2006) SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Am J Hum Genet 78:179–192PubMedCrossRef

11.

Lorenz-Depiereux B, et-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, Gershoni-Baruch R, Albers N, Lichtner P, Schnabel D, Hochberg Z, Strom TM (2006) Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am J Hum Genet 78:193–201PubMedCrossRef

12.

Segawa H, Aranami F, Kaneko I, Tomoe Y, Miyamoto K (2009) The roles of Na/Pi-II transporters in phosphate metabolism. Bone 45(Suppl 1):S2–S7PubMedCrossRef

13.

Kavanaugh MP, Miller DG, Zhang W, Law W, Kozak SL, Kabat D, Miller AD (1994) Cell-surface receptors for gibbon ape leukemia virus and amphotropic murine retrovirus are inducible sodium-dependent phosphate symporters. Proc Natl Acad Sci U S A 91:7071–7075PubMedCrossRef

14.

Miller DG, Miller AD (1994) A family of retroviruses that utilize related phosphate transporters for cell entry. J Virol 68:8270–8276PubMed

15.

Villa-Bellosta R, Ravera S, Sorribas V, Stange G, Levi M, Murer H, Biber J, Forster IC (2009) The Na + -Pi cotransporter PiT-2 (SLC20A2) is expressed in the apical membrane of rat renal proximal tubules and regulated by dietary Pi. Am J Physiol Renal Physiol 296:F691–F699PubMedCrossRef

16.

Breusegem SY, Takahashi H, Giral-Arnal H, Wang X, Jiang T, Verlander JW, Wilson P, Miyazaki-Anzai S, Sutherland E, Caldas Y, Blaine JT, Segawa H, Miyamoto K, Barry NP, Levi M (2009) Differential regulation of the renal sodium-phosphate cotransporters NaPi-IIa, NaPi-IIc, and PiT-2 in dietary potassium deficiency. Am J Physiol Renal Physiol 297:F350–F361PubMedCrossRef

17.

Villa-Bellosta R, Sorribas V (2010) Compensatory regulation of the sodium/phosphate cotransporters NaPi-IIc (SCL34A3) and Pit-2 (SLC20A2) during Pi deprivation and acidosis. Pflugers Arch 459:499–508PubMedCrossRef

18.

Miedlich SU, Zhu ED, Sabbagh Y, Demay MB (2010) The receptor-dependent actions of 1,25-dihydroxyvitamin D are required for normal growth plate maturation in NPt2a knockout mice. Endocrinology 151:4607–4612PubMedCrossRef

19.

Iwaki T, Sandoval-Cooper MJ, Tenenhouse HS, Castellino FJ (2008) A missense mutation in the sodium phosphate co-transporter Slc34a1 impairs phosphate homeostasis. J Am Soc Nephrol 19:1753–1762PubMedCrossRef

20.

Prie D, Huart V, Bakouh N, Planelles G, Dellis O, Gerard B, Hulin P, que-Blanchet F, Silve C, Grandchamp B, Friedlander G (2002) Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N Engl J Med 347:983–991PubMedCrossRef

21.

Virkki LV, Forster IC, Hernando N, Biber J, Murer H (2003) Functional characterization of two naturally occurring mutations in the human sodium-phosphate cotransporter type IIa. J Bone Miner Res 18:2135–2141PubMedCrossRef

22.

Lapointe JY, Tessier J, Paquette Y, Wallendorff B, Coady MJ, Pichette V, Bonnardeaux A (2006) NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak. Kidney Int 69:2261–2267PubMedCrossRef

23.

Magen D, Berger L, Coady MJ, Ilivitzki A, Militianu D, Tieder M, Selig S, Lapointe JY, Zelikovic I, Skorecki K (2010) A loss-of-function mutation in NaPi-IIa and renal Fanconi’s syndrome. N Engl J Med 362:1102–1109PubMedCrossRef

24.

Tieder M, Modai D, Samuel R, Arie R, Halabe A, Bab I, Gabizon D, Liberman UA (1985) Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med 312:611–617PubMedCrossRef

25.

Hernando N, Gisler SM, Pribanic S, Deliot N, Capuano P, Wagner CA, Moe OW, Biber J, Murer H (2005) NaPi-IIa and interacting partners. J Physiol 567:21–26PubMedCrossRef

26.

Cunningham R, Biswas RS, Steplock D, Shenolikar S, Weinman EJ (2010) Role of NHERF and scaffolding proteins in proximal tubule transport. Urol Res 4:257–262CrossRef

27.

Karim Z, Gerard B, Bakouh N, Alili R, Leroy C, Beck L, Silve C, Planelles G, Urena-Torres P, Grandchamp B, Friedlander G, Prie D (2008) NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med 359:1128–1135PubMedCrossRef

28.

Cai Q, Hodgson SF, Kao PC, Lennon VA, Klee GG, Zinsmiester AR, Kumar R (1994) Brief report: inhibition of renal phosphate transport by a tumor product in a patient with oncogenic osteomalacia. N Engl J Med 330:1645–1649PubMedCrossRef

29.

Econs MJ, Drezner MK (1994) Tumor-induced osteomalacia–unveiling a new hormone. N Engl J Med 330:1679–1681PubMedCrossRef

30.

Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T (2001) Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A 98:6500–6505PubMedCrossRef

31.

Liu S, Guo R, Simpson LG, Xiao ZS, Burnham CE, Quarles LD (2003) Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem 278:37419–37426PubMedCrossRef

32.

Mirams M, Robinson BG, Mason RS, Nelson AE (2004) Bone as a source of FGF23: regulation by phosphate? Bone 35:1192–1199PubMedCrossRef

33.

Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML, Goetz R, Mohammadi M, Baum M (2009) FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 297:F282–F291PubMedCrossRef

34.

Gattineni J, Baum M (2010) Regulation of phosphate transport by fibroblast growth factor 23 (FGF23): implications for disorders of phosphate metabolism. Pediatr Nephrol 25:591–601PubMedCrossRef

35.

Bai XY, Miao D, Goltzman D, Karaplis AC (2003) The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency. J Biol Chem 278:9843–9849PubMedCrossRef

36.

Sitara D, Razzaque MS, Hesse M, Yoganathan S, Taguchi T, Erben RG, Juppner H, Lanske B (2004) Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 23:421–432PubMedCrossRef

37.

Perwad F, Azam N, Zhang MY, Yamashita T, Tenenhouse HS, Portale AA (2005) Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology 146:5358–5364PubMedCrossRef

38.

Burnett SM, Gunawardene SC, Bringhurst FR, Juppner H, Lee H, Finkelstein JS (2006) Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Miner Res 21:1187–1196PubMedCrossRef

39.

Ferrari SL, Bonjour JP, Rizzoli R (2005) Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab 90:1519–1524PubMedCrossRef

40.

Saito H, Maeda A, Ohtomo S, Hirata M, Kusano K, Kato S, Ogata E, Segawa H, Miyamoto K, Fukushima N (2005) Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem 280:2543–2549PubMedCrossRef

41.

Li H, Martin AC, David V, Quarles LD (2010) Compound Deletion of FGFR3 and FGFR4 Partially Rescues the Hyp Mouse Phenotype. Am J Physiol Endocrinol Metab 300:E508–517

42.

Gattineni J, Twombley K, Goetz R, Mohammadi M, Baum M (2011) Regulation of serum 1,25(OH)2vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4. Am J Physiol Renal Physiol 301:F371–F377PubMedCrossRef

43.

Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51PubMedCrossRef

44.

Alon US (2011) Clinical practice. Fibroblast growth factor (FGF)23: a new hormone. Eur J Pediatr 170:545–554PubMedCrossRef

45.

Biber J, Hernando N, Forster I, Murer H (2009) Regulation of phosphate transport in proximal tubules. Pflugers Arch 458:39–52PubMedCrossRef

46.

Bianchine JW, Stambler AA, Harrison HE (1971) Familial hypophosphatemic rickets showing autosomal dominant inheritance. Birth Defects Orig Artic Ser 7:287–295PubMed

47.

ADHR Consortium (2000) Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26:345–348CrossRef

48.

Econs MJ, McEnery PT (1997) Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab 82:674–681PubMedCrossRef

49.

Imel EA, Hui SL, Econs MJ (2007) FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J Bone Miner Res 22:520–526PubMedCrossRef

50.

HYPOPHOSPHATEMIC RICKETS, X-LINKED DOMINANT; XLHR. OMIM . 1-13-2011. Ref Type: Electronic Citation http://www.omim.org/entry/307800

51.

Winters RW, Graham JB, Williams TF, McFalls VW, Burnett CH (1958) (1991) A genetic study of familial hypophosphatemia and vitamin D resistant rickets with a review of the literature. Medicine (Baltimore) 70:215–217

52.

Morgan JM, Hawley WL, Chenoweth AI, Retan WJ, Diethelm AG (1974) Renal transplantation in hypophosphatemia with vitamin D-resistant rickets. Arch Intern Med 134:549–552PubMedCrossRef

53.

Marie PJ, Travers R, Glorieux FH (1981) Mineral and skeletal changes in parabiotic normal and hypophosphatemic mice. Clin Res 29:414a

54.

Nesbitt T, Coffman TM, Griffiths R, Drezner MK (1992) Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect. J Clin Invest 89:1453–1459PubMedCrossRef

55.

Meyer RA Jr, Meyer MH, Gray RW (1989) Parabiosis suggests a humoral factor is involved in X-linked hypophosphatemia in mice. J Bone Miner Res 4:493–500PubMedCrossRef

56.

HYP Consortium (1995) A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium. Nat Genet 11:130–136CrossRef

57.

Du L, Desbarats M, Viel J, Glorieux FH, Cawthorn C, Ecarot B (1996) cDNA cloning of the murine Pex gene implicated in X-linked hypophosphatemia and evidence for expression in bone. Genomics 36:22–28PubMedCrossRef

58.

Farrow EG, White KE (2010) Recent advances in renal phosphate handling. Nat Rev Nephrol 6:207–217PubMedCrossRef

59.

Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD (2006) Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab 291:E38–E49PubMedCrossRef

60.

Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, Takeuchi Y, Fujita T, Nakahara K, Yamashita T, Fukumoto S (2002) Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab 87:4957–4960PubMedCrossRef

61.

Aono Y, Yamazaki Y, Yasutake J, Kawata T, Hasegawa H, Urakawa I, Fujita T, Wada M, Yamashita T, Fukumoto S, Shimada T (2009) Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia. J Bone Miner Res 24:1879–1888PubMedCrossRef

62.

Alon U, Donaldson DL, Hellerstein S, Warady BA, Harris DJ (1992) Metabolic and histologic investigation of the nature of nephrocalcinosis in children with hypophosphatemic rickets and in the Hyp mouse. J Pediatr 120:899–905PubMedCrossRef

63.

Cho HY, Lee BH, Kang JH, Ha IS, Cheong HI, Choi Y (2005) A clinical and molecular genetic study of hypophosphatemic rickets in children. Pediatr Res 58:329–333PubMedCrossRef

64.

Alon US, Levy-Olomucki R, Moore WV, Stubbs J, Liu S, Quarles LD (2008) Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets. Clin J Am Soc Nephrol 3:658–664PubMedCrossRef

65.

Perry W, Stamp TC (1978) Hereditary hypophosphataemic rickets with autosomal recessive inheritance and severe osteosclerosis. A report of two cases. J Bone Joint Surg Br 60-B:430–434PubMed

66.

Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V, Manor E, Buriakovsky S, Hadad Y, Goding J, Parvari R (2010) Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet 86:273–278PubMedCrossRef

67.

Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Hohne W, Schauer G, Lehmann M, Roscioli T, Schnabel D, Epplen JT, Knisely A, Superti-Furga A, McGill J, Filippone M, Sinaiko AR, Vallance H, Hinrichs B, Smith W, Ferre M, Terkeltaub R, Nurnberg P (2003) Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet 34:379–381PubMedCrossRef

68.

Imel EA, Econs MJ (2007) Fibrous dysplasia, phosphate wasting and fibroblast growth factor 23. Pediatr Endocrinol Rev 4(Suppl 4):434–439PubMed

69.

Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM (1991) Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 325:1688–1695PubMedCrossRef

70.

Yamamoto T, Imanishi Y, Kinoshita E, Nakagomi Y, Shimizu N, Miyauchi A, Satomura K, Koshiyama H, Inaba M, Nishizawa Y, Juppner H, Ozono K (2005) The role of fibroblast growth factor 23 for hypophosphatemia and abnormal regulation of vitamin D metabolism in patients with McCune-Albright syndrome. J Bone Miner Metab 23:231–237PubMedCrossRef

71.

White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S, Fields J, Yu X, Shaw NJ, McLellan NJ, McKeown C, Fitzpatrick D, Yu K, Ornitz DM, Econs MJ (2005) Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am J Hum Genet 76:361–367PubMedCrossRef

72.

Topaz O, Shurman DL, Bergman R, Indelman M, Ratajczak P, Mizrachi M, Khamaysi Z, Behar D, Petronius D, Friedman V, Zelikovic I, Raimer S, Metzker A, Richard G, Sprecher E (2004) Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet 36:579–581PubMedCrossRef

73.

et-Pages A, Orlik P, Strom TM, Lorenz-Depiereux B (2005) An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet 14:385–390CrossRef

74.

Ichikawa S, Imel EA, Kreiter ML, Yu X, Mackenzie DS, Sorenson AH, Goetz R, Mohammadi M, White KE, Econs MJ (2007) A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 117:2684–2691PubMedCrossRef

75.

Brownstein CA, Adler F, Nelson-Williams C, Iijima J, Li P, Imura A, Nabeshima Y, Reyes-Mugica M, Carpenter TO, Lifton RP (2008) A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci U S A 105:3455–3460PubMedCrossRef

76.

Kaufmann M, Muff R, Stieger B, Biber J, Murer H, Fischer JA (1994) Apical and basolateral parathyroid hormone receptors in rat renal cortical membranes. Endocrinology 134:1173–1178PubMedCrossRef

77.

Schipani E, Kruse K, Juppner H (1995) A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 268:98–100PubMedCrossRef

78.

Blomstrand S, Claesson I, Save-Soderbergh J (1985) A case of lethal congenital dwarfism with accelerated skeletal maturation. Pediatr Radiol 15:141–143PubMedCrossRef

79.

Scambler PJ, Carey AH, Wyse RK, Roach S, Dumanski JP, Nordenskjold M, Williamson R (1991) Microdeletions within 22q11 associated with sporadic and familial DiGeorge syndrome. Genomics 10:201–206PubMedCrossRef

80.

Markowitz GS, Stokes MB, Radhakrishnan J, D’Agati VD (2005) Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. J Am Soc Nephrol 16:3389–3396PubMedCrossRef

81.

Shiber JR, Mattu A (2002) Serum phosphate abnormalities in the emergency department. J Emerg Med 23:395–400PubMedCrossRef

82.

Neven E, D’Haese PC (2011) Vascular calcification in chronic renal failure: what have we learned from animal studies? Circ Res 108:249–264PubMedCrossRef

Title: Genetic disorders of phosphate regulation
Authors: Jyothsna Gattineni
Michel Baum
Publication date: 01-09-2012
Publisher: Springer-Verlag
Published in: Pediatric Nephrology / Issue 9/2012
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-012-2103-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Genetic disorders of phosphate regulation

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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