Abstract
To date, two responsible genes for the development of Dent disease have been identified: CLCN5 and OCRL1. In this study, genotype-phenotype correlations were studied in patients with Dent disease and those with Lowe syndrome. Among the 12 boys with a phenotype typical of Dent disease, nine had a mutation in CLCN5 (Dent disease 1), two had a mutation in OCRL1 (Dent disease 2), and one had no mutations in either gene. All seven boys with a clinical diagnosis of Lowe syndrome had a mutation in OCRL1. Patients with Lowe syndrome showed more frequent hypophosphatemia/rickets and more prominent tubular proteinuria than patients with Dent disease 1, and patients with Dent disease 2 had higher degree of tubular proteinuria and hypercalciuria than patients with Dent disease 1. Additionally, one patient with Dent disease 2 showed a mild degree of developmental delay, elevated serum muscle enzyme levels, and cryptorchidism. In this study, the genetic heterogeneity in Dent disease and the phenotypic heterogeneity in Lowe syndrome were confirmed. In patients with Dent disease, the presence of the above-mentioned extrarenal manifestations indicates that it is more likely that the patient is affected by Dent disease 2 than by Dent disease 1.
Similar content being viewed by others
References
Frymoyer PA, Scheinman SJ, Dunham PB, Jones DB, Hueber P, Schroeder ET (1991) X-linked recessive nephrolithiasis with renal failure. N Engl J Med 325:681–686
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 87:473–493
Scheinman SJ (1998) X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int 53:3–17
Thakker RV (2000) Pathogenesis of Dent’s disease and related syndromes of X-linked nephrolithiasis. Kidney Int 57:787–793
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 379:445–449
Hoopes RR, Raja KM, Koich A, Hueber P, Reid R, Knohl SJ, Scheinman SJ (2004) Evidence for genetic heterogeneity in Dent’s disease. Kidney Int 65:1615–1620
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 52:911–916
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 76:260–267
Utsch B, Bokenkamp A, Benz MR, Besbas N, Dotsch J, Franke I, Frund S, Gok F, Hoppe B, Karle S, Kuwertz-Broking 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 48:942–954
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 22:975–980
Pendaries C, Tronchere H, Plantavid M, Payrastre B (2003) Phosphoinositide signaling disorders in human diseases. FEBS Lett 546:25–31
McSpadden K (2000) Living with Lowe Syndrome: a guide for families, friends and professionals, 3rd edn. Lowe Syndrome Association, Inc
Matos V, van Melle G, Boulat O, Markert M, Bachmann C, Guignard JP (1997) Urinary phosphate/creatinine, calcium/creatinine, and magnesium/creatinine ratios in a healthy pediatric population. J Pediatr 131:252–257
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 20:455–459
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 21:2452–2463
Laube GF, Russell-Eggitt IM, van’t Hoff WG (2004) Early proximal tubular dysfunction in Lowe’s syndrome. Arch Dis Child 89:479–480
Lowe CU, Terry M, LacLachlan EA (1952) Organic aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation; clinical entity. Am J Dis Child 83:164–184
Sliman GA, Winters WD, Shaw DW, Avner ED (1995) Hypercalciuria and nephrocalcinosis in the oculocerebrorenal syndrome. J Urol 153:1244–1246
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 8:247–257
Piwon N, Gunther W, Schwake M, Bosl MR, Jentsch TJ (2000) ClC-5 Cl−channel disruption impairs endocytosis in a mouse model for Dent’s disease. Nature 408:369–373
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 9:2937–2945
Lowe M (2005) Structure and function of the Lowe syndrome protein OCRL1. Traffic 6:711–719
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 100:8472–8477
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 358:239–242
Zhang X, Jefferson AB, Auethavekiat V, Majerus PW (1995) The protein deficient in Lowe syndrome is a phosphatidylinositol-4,5-bisphosphate 5-phosphatase. Proc Natl Acad Sci USA 92:4853–4856
Janne PA, Suchy SF, Bernard D, MacDonald M, Crawley J, Grinberg A, Wynshaw-Boris A, Westphal H, Nussbaum RL (1998) Functional overlap between murine Inpp5b and Ocrl1 may explain why deficiency of the murine ortholog for OCRL1 does not cause Lowe syndrome in mice. J Clin Invest 101:2042–2253
Acknowledgment
This study was supported by a grant (04-2006-104-0) from Seoul National University Hospital.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Cho, H.Y., Lee, B.H., Choi, H.J. et al. Renal manifestations of Dent disease and Lowe syndrome. Pediatr Nephrol 23, 243–249 (2008). https://doi.org/10.1007/s00467-007-0686-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-007-0686-9