Pediatric Nephrology

, Volume 26, Issue 5, pp 693–704 | Cite as

Dent’s disease: clinical features and molecular basis

  • Félix Claverie-Martín
  • Elena Ramos-Trujillo
  • Víctor García-Nieto
Educational Review


Dent’s disease is an X-linked recessive renal tubulopathy characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure. LMWP is the most constant feature, while the other clinical manifestations show wide variability. Patients also present variable manifestations of proximal tubule dysfunctions, such as aminoaciduria, glucosuria, hyperphosphaturia, kaliuresis, and uricosuria, consistent with renal Fanconi syndrome. Dent’s disease affects mainly male children, and female carriers are generally asymptomatic. In two-thirds of patients, the disease is caused by mutations in the CLCN5 gene, which encodes the electrogenic chloride/proton exchanger ClC-5. A few patients have mutations in OCRL1, the gene associated with the oculocerebrorenal syndrome of Lowe, which encodes a phosphatidylinositol-4,5-biphosphate-5-phosphatase (OCRL1). Both ClC-5 and OCRL1 are involved in the endocytic pathway for reabsorption of LMW proteins in the proximal tubule. This review will provide an overview of the important phenotypic characteristics of Dent’s disease and summarize the molecular data that have significantly increased our comprehension of the mechanisms causing this disease.


Proximal tubular disorder  Nephrocalcinosis  Nephrolithiasis  Endocytosis  Genetic disease CLCN5 OCRL1 



Funding grants PI09/91009 and PI 17/09 were received from the “Fondo de Investigación Sanitaria” and “Fundación Canaria de Investigación y Salud FUNCIS”, respectively.

Conflict of interest statement

The authors declare that they have no conflict of interest.


  1. 1.
    Dent CE, Friedman M (1964) Hypercalcuric rickets associated with renal tubular damage. Arch Dis Child 39:240–249PubMedGoogle Scholar
  2. 2.
    Wrong OM, Norden AG, Feest TG (1994) Dent's disease; a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive renal failure and a marked male predominance. Q J Med 87:473–493Google Scholar
  3. 3.
    Frymoyer PA, Scheinman SJ, Dunham PB, Jones DB, Hueber P, Schroeder ET (1991) X-linked recessive nephrolithiasis with renal failure. N Engl J Med 325:681–686PubMedGoogle Scholar
  4. 4.
    Pook MA, Wrong O, Wooding C, Norden AG, Feest TG, Thakker RV (1993) Dent's disease, a renal Fanconi syndrome with nephrocalcinosis and kidney stones, is associated with a microdeletion involving DXS255 and maps to Xp11.22. Hum Mol Genet 2:2129–2134PubMedGoogle Scholar
  5. 5.
    Scheinman SJ, Pook MA, Wooding C, Pang JT, Frymoyer PA, Thakker RV (1993) Mapping the gene causing X-linked recessive nephrolithiasis to Xp11.22 by linkage studies. J Clin Invest 9:2351–2357Google Scholar
  6. 6.
    Bolino A, Devoto M, Enia G, Zoccali C, Weissenbach J, Romeo G (1993) Genetic mapping in the Xp11.2 region of a new form of X-linked hypophosphatemic rickets. Eur J Hum Genet 1:269–279PubMedGoogle Scholar
  7. 7.
    Igarashi T, Hayakawa H, Shiraga H, Kawato H, Yan K, Kawaguchi H, Yamanaka T, Tsuchida S, Akagi K (1995) Hypercalciuria and nephrocalcinosis in patients with idiopathic low-molecular-weight proteinuria in Japan: is the disease identical to Dent's disease in the United Kingdom? Nephron 69:242–247PubMedGoogle Scholar
  8. 8.
    Lloyd SE, Pearce SH, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, Harding B, Bolino A, Devoto M, Goodyer P, Rigden SP, Wrong O, Jentsch TJ, Craig IW, Thakker RV (1996) A common molecular basis for three inherited kidney stone diseases. Nature 379:445–449PubMedGoogle Scholar
  9. 9.
    Lloyd SE, Gunther W, Pearce SH, Thomson A, Bianchi ML, Bosio M, Craig IW, Fisher SE, Scheinman SJ, Wrong O, Jentsch TJ, Thakker RV (1997) Characterisation of renal chloride channel, CLCN5, mutations in hypercalciuric nephrolithiasis (kidney stones) disorders. Hum Mol Genet 6:1233–1239PubMedGoogle Scholar
  10. 10.
    Picollo A, Pusch M (2005) Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5. Nature 436:420–423PubMedGoogle Scholar
  11. 11.
    Scheel O, Zdebik AA, Lourdel S, Jentsch TJ (2005) Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins. Nature 436:424–427PubMedGoogle Scholar
  12. 12.
    Piwon N, Günther W, Schwake M, Bösl MR, Jentsch TJ (2000) ClC-5 Cl--channel disruption impairs endocytosis in a mouse model for Dent's disease. Nature 408:369–373PubMedGoogle Scholar
  13. 13.
    Wang SS, Devuyst O, Courtoy PJ, Wang XT, Wang H, Wang Y, Thakker RV, Guggino S, Guggino WB (2000) Mice lacking renal chloride channel, CLC-5, are a model for Dent's disease, a nephrolithiasis disorder associated with defective receptor-mediated endocytosis. Hum Mol Genet 9:2937–2945PubMedGoogle Scholar
  14. 14.
    Guggino SE (2007) Mechanisms of disease: what can mouse models tell us about the molecular processes underlying Dent disease? Nat Clin Pract Nephrol 3:449–455PubMedGoogle Scholar
  15. 15.
    Plans V, Rickheit G, Jentsch TJ (2009) Physiological roles of CLC Cl(-)/H (+) exchangers in renal proximal tubules. Pflugers Arch 458:23–37PubMedGoogle Scholar
  16. 16.
    Hoopes RR Jr, Shrimpton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, Simckes A, Tasic V, Toenshoff B, Suchy SF, Nussbaum RL, Scheinman SJ (2005) Dent disease with mutations in OCRL1. Am J Hum Genet 76:260–267PubMedGoogle Scholar
  17. 17.
    Choudhury R, Diao A, Zhang F, Eisenberg E, Saint-Pol A, Williams C, Konstantakopoulos A, Lucocq J, Johannes L, Rabouille C, Greene LE, Lowe M (2005) Lowe syndrome protein OCRL1 interacts with clathrin and regulates protein trafficking between endosomes and the trans-Golgi network. Mol Biol Cell 16:3467–3479PubMedGoogle Scholar
  18. 18.
    Lowe M (2005) Structure and function of the Lowe syndrome protein OCRL1. Traffic 6:711–719PubMedGoogle Scholar
  19. 19.
    Ooms LM, Horan KA, Rahman P, Seaton G, Gurung R, Kethesparan DS, Mitchell CA (2009) The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease. Biochem J 419:29–49PubMedGoogle Scholar
  20. 20.
    Ludwig M, Utsch B, Monnens LA (2006) Recent advances in understanding the clinical and genetic heterogeneity of Dent's disease. Nephrol Dial Transplant 21:2708–2717PubMedGoogle Scholar
  21. 21.
    Cox JP, Yamamoto K, Christie PT, Wooding C, Feest T, Flinter FA, Goodyer PR, Leumann E, Neuhaus T, Reid C, Williams PF, Wrong O, Thakker RV (1999) Renal chloride channel, CLCN5, mutations in Dent's disease. J Bone Miner Res 14:1536–1542PubMedGoogle Scholar
  22. 22.
    Vezzoli G, Corghi E, Edefonti A, Palazzi P, Dell'Antonio G, Elli A, Azzani T, Vallino F, Bianchi G (1995) Nonacidotic kidney proximal tubulopathy with absorptive hypercalciuria. Am J Kidney Dis 25:222–227PubMedGoogle Scholar
  23. 23.
    Carballo-Trujillo I, Garcia-Nieto V, Moya-Angeler FJ, Antón-Gamero M, Loris C, Méndez-Alvarez S, Claverie-Martin F (2003) Novel truncating mutations in the ClC-5 chloride channel gene in patients with Dent's disease. Nephrol Dial Transplant 18:717–723PubMedGoogle Scholar
  24. 24.
    Reinhart SC, Norden AG, Lapsley M, Thakker RV, Pang J, Moses AM, Frymoyer PA, Favus MJ, Hoepner JA, Scheinman SJ (1995) Characterization of carrier females and affected males with X-linked recessive nephrolithiasis. J Am Soc Nephrol 5:1451–1461PubMedGoogle Scholar
  25. 25.
    Hoopes RR Jr, Hueber PA, Reid RJ Jr, Braden GL, Goodyer PR, Melnyk AR, Midgley JP, Moel DI, Neu AM, VanWhy SK, Scheinman SJ (1998) CLCN5 chloride-channel mutations in six new North American families with X-linked nephrolithiasis. Kidney Int 54:698–705PubMedGoogle Scholar
  26. 26.
    Scheinman SJ (1998) X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int 53:3–17PubMedGoogle Scholar
  27. 27.
    Scheinman SJ, Cox JP, Lloyd SE, Pearce SH, Salenger PV, Hoopes RR, Bushinsky DA, Wrong O, Asplin JR, Langman CB, Norden AG, Thakker RV (2000) Isolated hypercalciuria with mutation in CLCN5: relevance to idiopathic hypercalciuria. Kidney Int 57:232–239PubMedGoogle Scholar
  28. 28.
    Norden AG, Lapsley M, Lee PJ, Pusey CD, Scheinman SJ, Tam FW, Thakker RV, Unwin RJ, Wrong O (2001) Glomerular protein sieving and implications for renal failure in Fanconi syndrome. Kidney Int 60:1885–1892PubMedGoogle Scholar
  29. 29.
    Antón-Gamero M, Claverie-Martín F, García-Nieto V, Vela-Enríquez F, García-Martínez E, Pérez-Navero JL (2005) Chloride and sodium renal tubular handling in Dent's disease. Pediatr Nephrol 20:1198–1199PubMedGoogle Scholar
  30. 30.
    Scheinman SJ (2009) Dent’s disease. In: Lifton RP, Somlo S, Giebisch GH, Seldin DW (eds) Genetic diseases of the kidney, 1st edn. Academic Press, New York, pp 213–226Google Scholar
  31. 31.
    Bökenkamp A, Böckenhauer D, Cheong HI, Hoppe B, Tasic V, Unwin R, Ludwig M (2009) Dent-2 disease: a mild variant of Lowe syndrome. J Pediatr 155:94–99PubMedGoogle Scholar
  32. 32.
    Cebotaru V, Kaul S, Devuyst O, Cai H, Racusen L, Guggino WB, Guggino SE (2005) High citrate diet delays progression of renal insufficiency in the ClC-5 knockout mouse model of Dent's disease. Kidney Int 68:642–652PubMedGoogle Scholar
  33. 33.
    Silva IV, Cebotaru V, Wang H, Wang XT, Wang SS, Guo G, Devuyst O, Thakker RV, Guggino WB, Guggino SE (2003) The ClC-5 knockout mouse model of Dent's disease has renal hypercalciuria and increased bone turnover. J Bone Miner Res 18:615–623PubMedGoogle Scholar
  34. 34.
    Sayer JA, Carr G, Simmons NL (2004) Calcium phosphate and calcium oxalate crystal handling is dependent upon CLC-5 expression in mouse collecting duct cells. Biochim Biophys Acta 1689:83–90PubMedGoogle Scholar
  35. 35.
    Sayer JA, Carr G, Simmons NL (2004) Nephrocalcinosis: molecular insights into calcium precipitation within the kidney. Clin Sci (Lond) 106:549–561Google Scholar
  36. 36.
    Tosetto E, Graziotto R, Artifoni L, Nachtigal J, Cascone C, Conz P, Piva M, Dell'Aquila R, De Paoli VE, Citron L, Nalesso F, Antonello A, Vertolli U, Zagatti R, Lupo A, D'Angelo A, Anglani F, Gambaro G (2006) Dent's disease and prevalence of renal stones in dialysis patients in Northeastern Italy. J Hum Genet 51:25–30PubMedGoogle Scholar
  37. 37.
    Hoopes RR Jr, Raja KM, Koich A, Hueber P, Reid R, Knohl SJ, Scheinman SJ (2004) Evidence for genetic heterogeneity in Dent's disease. Kidney Int 65:1615–1620PubMedGoogle Scholar
  38. 38.
    Murakami T, Kawakami H (1990) The clinical significance of asymptomatic low molecular weight proteinuria detected on routine screening of children in Japan: a survey of 53 patients. Clin Nephrol 33:12–19PubMedGoogle Scholar
  39. 39.
    Langlois V, Bernard C, Scheinman SJ, Thakker RV, Cox JP, Goodyer PR (1998) Clinical features of X-linked nephrolithiasis in childhood. Pediatr Nephrol 12:625–629PubMedGoogle Scholar
  40. 40.
    Moulin P, Igarashi T, Van der Smissen P, Cosyns JP, Verroust P, Thakker RV, Scheinman SJ, Courtoy PJ, Devuyst O (2003) Altered polarity and expression of H + -ATPase without ultrastructural changes in kidneys of Dent's disease patients. Kidney Int 63:1285–1295PubMedGoogle Scholar
  41. 41.
    Hodgin JB, Corey HE, Kaplan BS, D'Agati VD (2008) Dent disease presenting as partial Fanconi syndrome and hypercalciuria. Kidney Int 73:1320–1323PubMedGoogle Scholar
  42. 42.
    Copelovitch L, Nash MA, Kaplan BS (2007) Hypothesis: Dent disease is an underrecognized cause of focal glomerulosclerosis. Clin J Am Soc Nephrol 2:914–918PubMedGoogle Scholar
  43. 43.
    Frishberg Y, Dinour D, Belostotsky R, Becker-Cohen R, Rinat C, Feinstein S, Navon-Elkan P, Ben-Shalom E (2009) Dent's disease manifesting as focal glomerulosclerosis: Is it the tip of the iceberg? Pediatr Nephrol 24:2369–2373PubMedGoogle Scholar
  44. 44.
    Raja KA, Schurman S, D'mello RG, Blowey D, Goodyer P, Van Why S, Ploutz-Snyder RJ, Asplin J, Scheinman SJ (2002) Responsiveness of hypercalciuria to thiazide in Dent's disease. J Am Soc Nephrol 13:2938–2944PubMedGoogle Scholar
  45. 45.
    Monroy A, Plata C, Hebert SC, Gamba G (2000) Characterization of the thiazide-sensitive Na + Cl--cotransporter: a new model for ions and diuretics interaction. Am J Physiol Renal Physiol 279:F161–F169PubMedGoogle Scholar
  46. 46.
    Nijenhuis T, Vallon V, van der Kemp AW, Loffing J, Hoenderop JG, Bindels RJ (2005) Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest 115:1651–1658PubMedGoogle Scholar
  47. 47.
    Blanchard A, Vargas-Poussou R, Peyrard S, Mogenet A, Baudouin V, Boudailliez B, Charbit M, Deschesnes G, Ezzhair N, Loirat C, Macher MA, Niaudet P, Azizi M (2008) Effect of hydrochlorothiazide on urinary calcium excretion in Dent disease: an uncontrolled trial. Am J Kidney Dis 52:1084–1095PubMedGoogle Scholar
  48. 48.
    Fisher SE, Black GC, Lloyd SE, Hatchwell E, Wrong O, Thakker RV, Craig IW (1994) Isolation and partial characterization of a chloride channel gene which is expressed in kidney and is a candidate for Dent's disease (an X-linked hereditary nephrolithiasis). Hum Mol Genet 3:2053–2059PubMedGoogle Scholar
  49. 49.
    Fisher SE, van Bakel I, Lloyd SE, Pearce SH, Thakker RV, Craig IW (1995) Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis). Genomics 29:598–606PubMedGoogle Scholar
  50. 50.
    Attree O, Olivos IM, Okabe I, Bailey LC, Nelson DL, Lewis RA, McInnes RR, Nussbaum RL (1992) The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase. Nature 358:239–242PubMedGoogle Scholar
  51. 51.
    Nussbaum RL, Orrison BM, Jänne PA, Charnas L, Chinault AC (1997) Physical mapping and genomic structure of the Lowe syndrome gene OCRL1. Hum Genet 99:145–150PubMedGoogle Scholar
  52. 52.
    Coca SG, Reilly RF (2009) The oculocerebrorenal syndrome of Lowe. In: Lifton RP, Somlo S, Giebisch GH, Seldin DW (eds) Genetics disease of the kidney, 1st edn. Academic Press, New York, pp 587–596Google Scholar
  53. 53.
    Lowe CU, Terrey M, MacLachlan EA (1952) Organic-aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation; a clinical entity. AMA Am J Dis Child 83:164–184PubMedGoogle Scholar
  54. 54.
    Bockenhauer D, Bokenkamp A, van't Hoff W, Levtchenko E, Kist-van Holthe JE, Tasic V, Ludwig M (2008) Renal phenotype in Lowe Syndrome: a selective proximal tubular dysfunction. Clin J Am Soc Nephrol 3:1430–1436PubMedGoogle Scholar
  55. 55.
    Ludwig M, Utsch B (2004) Dent disease-like phenotype and the chloride channel ClC-4 (CLCN4) gene. Am J Med Genet 128A:434–435PubMedGoogle Scholar
  56. 56.
    Igarashi T, Günther W, Sekine T, Inatomi J, Shiraga H, Takahashi S, Suzuki J, Tsuru N, Yanagihara T, Shimazu M, Jentsch TJ, Thakker RV (1998) Functional characterization of renal chloride channel, CLCN5, mutations associated with Dent's Japan disease. Kidney Int 54:1850–1856PubMedGoogle Scholar
  57. 57.
    Jentsch TJ (2008) CLC chloride channels and transporters: from genes to protein structure, pathology and physiology. Crit Rev Biochem Mol Biol 43:3–36PubMedGoogle Scholar
  58. 58.
    Dutzler R, Campbell EB, Cadene M, Chait BT, MacKinnon R (2002) X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity. Nature 415:287–294PubMedGoogle Scholar
  59. 59.
    Ponting CP (1997) CBS domains in CIC chloride channels implicated in myotonia and nephrolithiasis (kidney stones). J Mol Med 75:160–163PubMedGoogle Scholar
  60. 60.
    Meyer S, Savaresi S, Forster IC, Dutzler R (2007) Nucleotide recognition by the cytoplasmic domain of the human chloride transporter ClC-5. Nat Struct Mol Biol 14:60–67PubMedGoogle Scholar
  61. 61.
    Schwake M, Friedrich T, Jentsch TJ (2001) An internalization signal in ClC-5, an endosomal Cl-channel mutated in Dent's disease. J Biol Chem 276:12049–12054PubMedGoogle Scholar
  62. 62.
    Steinmeyer K, Schwappach B, Bens M, Vandewalle A, Jentsch TJ (1995) Cloning and functional expression of rat CLC-5, a chloride channel related to kidney disease. J Biol Chem 270:31172–31177PubMedGoogle Scholar
  63. 63.
    Vandewalle A, Cluzeaud F, Peng KC, Bens M, Lüchow A, Günther W, Jentsch TJ (2001) Tissue distribution and subcellular localization of the ClC-5 chloride channel in rat intestinal cells. Am J Physiol Cell Physiol 280:C373–381PubMedGoogle Scholar
  64. 64.
    Günther W, Lüchow A, Cluzeaud F, Vandewalle A, Jentsch TJ (1998) ClC-5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells. Proc Natl Acad Sci USA 95:8075–8080PubMedGoogle Scholar
  65. 65.
    Devuyst O, Christie PT, Courtoy PJ, Beauwens R, Thakker RV (1999) Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease. Hum Mol Genet 8:247–257PubMedGoogle Scholar
  66. 66.
    Sakamoto H, Sado Y, Naito I, Kwon TH, Inoue S, Endo K, Kawasaki M, Uchida S, Nielsen S, Sasaki S, Marumo F (1999) Cellular and subcellular immunolocalization of ClC-5 channel in mouse kidney: colocalization with H + -ATPase. Am J Physiol 277:F957–965PubMedGoogle Scholar
  67. 67.
    Akuta N, Lloyd SE, Igarashi T, Shiraga H, Matsuyama T, Yokoro S, Cox JP, Thakker RV (1997) Mutations of CLCN5 in Japanese children with idiopathic low molecular weight proteinuria, hypercalciuria and nephrocalcinosis. Kidney Int 52:911–916PubMedGoogle Scholar
  68. 68.
    Cheong HI, Lee JW, Zheng SH, Lee JH, Kang JH, Kang HG, Ha IS, Lee SJ, Choi Y (2005) Phenotype and genotype of Dent's disease in three Korean boys. Pediatr Nephrol 20:455–459PubMedGoogle Scholar
  69. 69.
    Claverie-Martin F, González-Acosta H, Flores C, Antón-Gamero M, García-Nieto V (2003) De novo insertion of an Alu sequence in the coding region of the CLCN5 gene results in Dent's disease. Hum Genet 113:480–485PubMedGoogle Scholar
  70. 70.
    Ludwig M, Doroszewicz J, Seyberth HW, Bökenkamp A, Balluch B, Nuutinen M, Utsch B, Waldegger S (2005) Functional evaluation of Dent's disease-causing mutations: implications for ClC-5 channel trafficking and internalization. Hum Genet 117:228–237Google Scholar
  71. 71.
    Morimoto T, Uchida S, Sakamoto H, Kondo Y, Hanamizu H, Fukui M, Tomino Y, Nagano N, Sasaki S, Marumo F (1998) Mutations in CLCN5 chloride channel in Japanese patients with low molecular weight proteinuria. J Am Soc Nephrol 9:811–818PubMedGoogle Scholar
  72. 72.
    Tosetto E, Ghiggeri GM, Emma F, Barbano G, Carrea A, Vezzoli G, Torregrossa R, Cara M, Ripanti G, Ammenti A, Peruzzi L, Murer L, Ratsch IM, Citron L, Gambaro G, D'angelo A, Anglani F (2006) Phenotypic and genetic heterogeneity in Dent's disease—the results of an Italian collaborative study. Nephrol Dial Transplant 21:2452–2463PubMedGoogle Scholar
  73. 73.
    Ramos-Trujillo E, González-Acosta H, Flores C, García-Nieto V, Guillén E, Gracia S, Vicente C, Espinosa L, Maseda MA, Santos F, Camacho JA, Claverie-Martín F (2007) A missense mutation in the chloride/proton ClC-5 antiporter gene results in increased expression of an alternative mRNA form that lacks exons 10 and 11. Identification of seven new CLCN5 mutations in patients with Dent's disease. J Hum Genet 52:255–261PubMedGoogle Scholar
  74. 74.
    Ramos-Trujillo E, Garcia-Nieto V, Gonzalez-Acosta H, Vara J, Pérez-Diaz V, Nadal I, Oliveros R, Claverie-Martin F (2007) Molecular analysis of the CLCN5 gene in Dent's disease: first mutation identified in a patient from South America. Clin Nephrol 68:367–372PubMedGoogle Scholar
  75. 75.
    Grand T, Mordasini D, L'Hoste S, Pennaforte T, Genete M, Biyeyeme MJ, Vargas-Poussou R, Blanchard A, Teulon J, Lourdel S (2009) Novel CLCN5 mutations in patients with Dent's disease result in altered ion currents or impaired exchanger processing. Kidney Int 76:999–1005PubMedGoogle Scholar
  76. 76.
    Wu F, Roche P, Christie PT, Loh NY, Reed AA, Esnouf RM, Thakker RV (2003) Modeling study of human renal chloride channel (hCLC-5) mutations suggests a structural-functional relationship. Kidney Int 63:1426–1432PubMedGoogle Scholar
  77. 77.
    Smith AJ, Reed AA, Loh NY, Thakker RV, Lippiat JD (2009) Characterization of Dent's disease mutations of CLC-5 reveals a correlation between functional and cell biological consequences and protein structure. Am J Physiol Renal Physiol 296:F390–397PubMedGoogle Scholar
  78. 78.
    Cartegni L, Chew SL, Krainer AR (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 3:285–298PubMedGoogle Scholar
  79. 79.
    Batzer MA, Deininger PL (2002) Alu repeats and human genomic diversity. Nat Rev Genet 3:370–379PubMedGoogle Scholar
  80. 80.
    Claverie-Martín F, Flores C, Antón-Gamero M, González-Acosta H, García-Nieto V (2005) The Alu insertion in the CLCN5 gene of a patient with Dent's disease leads to exon 11 skipping. J Hum Genet 50:370–374PubMedGoogle Scholar
  81. 81.
    Thorleifsson G, Holm H, Edvardsson V, Walters GB, Styrkarsdottir U, Gudbjartsson DF, Sulem P, Halldorsson BV, de Vegt F, d'Ancona FC, den Heijer M, Franzson L, Christiansen C, Alexandersen P, Rafnar T, Kristjansson K, Sigurdsson G, Kiemeney LA, Bodvarsson M, Indridason OS, Palsson R, Kong A, Thorsteinsdottir U, Stefansson K (2009) Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density. Nat Genet 41:926–930PubMedGoogle Scholar
  82. 82.
    Raucher D, Stauffer T, Chen W, Shen K, Guo S, York JD, Sheetz MP, Meyer T (2000) Phosphatidylinositol 4, 5-bisphosphate functions as a second messenger that regulates cytoskeleton-plasma membrane adhesion. Cell 100:221–228PubMedGoogle Scholar
  83. 83.
    Olivos-Glander IM, Jänne PA, Nussbaum RL (1995) The oculocerebrorenal syndrome gene product is a 105-kD protein localized to the Golgi complex. Am J Hum Genet 57:817–823PubMedGoogle Scholar
  84. 84.
    Erb BC, Velázquez H, Gisser M, Shugrue CA, Reilly RF (1997) cDNA cloning and localization of OCRL-1 in rabbit kidney. Am J Physiol 273:F790–795PubMedGoogle Scholar
  85. 85.
    Hyvola N, Diao A, McKenzie E, Skippen A, Cockcroft S, Lowe M (2006) Membrane targeting and activation of the Lowe syndrome protein OCRL1 by rab GTPases. EMBO J 25:3750–3761PubMedGoogle Scholar
  86. 86.
    Ungewickell A, Ward ME, Ungewickell E, Majerus PW (2004) The inositol polyphosphate 5-phosphatase Ocrl associates with endosomes that are partially coated with clathrin. Proc Natl Acad Sci USA 101:13501–13506PubMedGoogle Scholar
  87. 87.
    Erdmann KS, Mao Y, McCrea HJ, Zoncu R, Lee S, Paradise S, Modregger J, Biemesderfer D, Toomre D, De Camilli P (2007) A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway. Dev Cell 13:377–390PubMedGoogle Scholar
  88. 88.
    Shrimpton AE, Hoopes RR Jr, Knohl SJ, Hueber P, Reed AA, Christie PT, Igarashi T, Lee P, Lehman A, White C, Milford DV, Sanchez MR, Unwin R, Wrong OM, Thakker RV, Scheinman SJ (2009) OCRL1 mutations in Dent 2 patients suggest a mechanism for phenotypic variability. Nephron Physiol 112:p27–36PubMedGoogle Scholar
  89. 89.
    Utsch B, Bökenkamp A, Benz MR, Besbas N, Dötsch J, Franke I, Fründ S, Gok F, Hoppe B, Karle S, Kuwertz-Bröking E, Laube G, Neb M, Nuutinen M, Ozaltin F, Rascher W, Ring T, Tasic V, van Wijk JA, Ludwig M (2006) Novel OCRL1 mutations in patients with the phenotype of Dent disease. Am J Kidney Dis 48:e1–14PubMedGoogle Scholar
  90. 90.
    Sekine T, Nozu K, Iyengar R, Fu XJ, Matsuo M, Tanaka R, Iijima K, Matsui E, Harita Y, Inatomi J, Igarashi T (2007) OCRL1 mutations in patients with Dent disease phenotype in Japan. Pediatr Nephrol 22:975–980PubMedGoogle Scholar
  91. 91.
    Cho HY, Lee BH, Choi HJ, Ha IS, Choi Y, Cheong HI (2008) Renal manifestations of Dent disease and Lowe syndrome. Pediatr Nephrol 23:243–249PubMedGoogle Scholar
  92. 92.
    McCrea HJ, Paradise S, Tomasini L, Addis M, Melis MA, De Matteis MA, De Camilli P (2008) All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding. Biochem Biophys Res Commun 369:493–499PubMedGoogle Scholar
  93. 93.
    Luyckx VA, Leclercq B, Dowland LK, Yu AS (1999) Diet-dependent hypercalciuria in transgenic mice with reduced CLC5 chloride channel expression. Proc Natl Acad Sci USA 96:12174–12179PubMedGoogle Scholar
  94. 94.
    Christensen EI, Birn H (2002) Megalin and cubilin: multifunctional endocytic receptors. Nat Rev Mol Cell Biol 3:256–266PubMedGoogle Scholar
  95. 95.
    Mellman I, Fuchs R, Helenius A (1986) Acidification of the endocytic and exocytic pathways. Annu Rev Biochem 55:663–700PubMedGoogle Scholar
  96. 96.
    Jentsch TJ (2007) Chloride and the endosomal-lysosomal pathway: emerging roles of CLC chloride transporters. J Physiol 578:633–640PubMedGoogle Scholar
  97. 97.
    Devuyst O, Jouret F, Auzanneau C, Courtoy PJ (2005) Chloride channels and endocytosis: new insights from Dent's disease and ClC-5 knockout mice. Nephron Physiol 99:69–73Google Scholar
  98. 98.
    Christensen EI, Devuyst O, Dom G, Nielsen R, Van der Smissen P, Verroust P, Leruth M, Guggino WB, Courtoy PJ (2003) Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules. Proc Natl Acad Sci USA 100:8472–8477PubMedGoogle Scholar
  99. 99.
    Hilpert J, Nykjaer A, Jacobsen C, Wallukat G, Nielsen R, Moestrup SK, Haller H, Luft FC, Christensen EI, Willnow TE (1999) Megalin antagonizes activation of the parathyroid hormone receptor. J Biol Chem 274:5620–5625PubMedGoogle Scholar
  100. 100.
    Murayama A, Takeyama K, Kitanaka S, Kodera Y, Kawaguchi Y, Hosoya T, Kato S (1999) Positive and negative regulations of the renal 25-hydroxyvitamin D3 1alpha-hydroxylase gene by parathyroid hormone, calcitonin, and 1alpha, 25(OH)2D3 in intact animals. Endocrinology 140:2224–2231PubMedGoogle Scholar
  101. 101.
    Devuyst O, Pirson Y (2007) Genetics of hypercalciuric stone forming diseases. Kidney Int 72:1065–1072PubMedGoogle Scholar
  102. 102.
    Hryciw DH, Wang Y, Devuyst O, Pollock CA, Poronnik P, Guggino WB (2003) Cofilin interacts with ClC-5 and regulates albumin uptake in proximal tubule cell lines. J Biol Chem 278:40169–40176PubMedGoogle Scholar
  103. 103.
    Hryciw DH, Ekberg J, Lee A, Lensink IL, Kumar S, Guggino WB, Cook DI, Pollock CA, Poronnik P (2004) Nedd4-2 functionally interacts with ClC-5: involvement in constitutive albumin endocytosis in proximal tubule cells. J Biol Chem 279:54996–55007PubMedGoogle Scholar
  104. 104.
    Hryciw DH, Ekberg J, Ferguson C, Lee A, Wang D, Parton RG, Pollock CA, Yun CC, Poronnik P (2006) Regulation of albumin endocytosis by PSD95/Dlg/ZO-1 (PDZ) scaffolds. Interaction of Na + -H + exchange regulatory factor-2 with ClC-5. J Biol Chem 281:16068–16077PubMedGoogle Scholar
  105. 105.
    Reed AA, Loh NY, Terryn S, Lippiat JD, Partridge C, Galvanovskis J, Williams SE, Jouret F, Wu FT, Courtoy PJ, Nesbit MA, Rorsman P, Devuyst O, Ashcroft FM, Thakker RV (2010) CLC-5 and KIF3B interact to facilitate CLC-5 plasma membrane expression, endocytosis, and microtubular transport: relevance to pathophysiology of Dent's disease. Am J Physiol Renal Physiol 298:F365–380PubMedGoogle Scholar
  106. 106.
    Novarino G, Weinert S, Rickheit G, Jentsch TJ (2010) Endosomal chloride-proton exchange rather than chloride conductance is crucial for renal endocytosis. Science 328:1398–1401PubMedGoogle Scholar
  107. 107.
    Accardi A, Miller C (2004) Secondary active transport mediated by a prokaryotic homologue of ClC Cl- channels. Nature 427:803–807PubMedGoogle Scholar
  108. 108.
    Zdebik AA, Zifarelli G, Bergsdorf EY, Soliani P, Scheel O, Jentsch TJ, Pusch M (2008) Determinants of anion-proton coupling in mammalian endosomal CLC proteins. J Biol Chem 283:4219–4227PubMedGoogle Scholar
  109. 109.
    Bergsdorf EY, Zdebik AA, Jentsch TJ (2009) Residues important for nitrate/proton coupling in plant and mammalian CLC transporters. J Biol Chem 284:11184–11193PubMedGoogle Scholar
  110. 110.
    Jänne PA, Suchy SF, Bernard D, MacDonald M, Crawley J, Grinberg A, Wynshaw-Boris A, Westphal H, Nussbaum RL (1998) Functional overlap between murine Inpp 5b and Ocrl1 may explain why deficiency of the murine ortholog for OCRL1 does not cause Lowe syndrome in mice. J Clin Invest 101:2042–2053PubMedGoogle Scholar
  111. 111.
    Ludwig M, Utsch B, Balluch B, Frund S, Kuwertz-Broking E, Bokenkamp A (2006) Hypercalciuria in patients with CLCN5 mutations. Pediatr Nephrol 21:1241–1250PubMedGoogle Scholar

Copyright information

© IPNA 2010

Authors and Affiliations

  • Félix Claverie-Martín
    • 1
  • Elena Ramos-Trujillo
    • 1
  • Víctor García-Nieto
    • 2
  1. 1.Unidad de InvestigaciónHospital Universitario Nuestra Señora de CandelariaSanta Cruz de TenerifeSpain
  2. 2.Unidad de Nefrología PediátricaHospital Universitario Nuestra Señora de CandelariaSanta Cruz de TenerifeSpain

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