Pediatric Nephrology

, Volume 24, Issue 10, pp 1967–1973

Locus heterogeneity of Dent’s disease: OCRL1 and TMEM27 genes in patients with no CLCN5 mutations

  • Enrica Tosetto
  • Maria Addis
  • Gianluca Caridi
  • Cristiana Meloni
  • Francesco Emma
  • Gianluca Vergine
  • Gilda Stringini
  • Teresa Papalia
  • Giancarlo Barbano
  • Gian Marco Ghiggeri
  • Laura Ruggeri
  • Nunzia Miglietti
  • Angela D′Angelo
  • Maria Antonietta Melis
  • Franca Anglani
Original Article

Abstract

Dent′s disease is an X-linked renal tubulopathy caused by mutations mainly affecting the CLCN5 gene. Defects in the OCRL1 gene, which is usually mutated in patients with Lowe syndrome, have recently been shown to lead to a Dent-like phenotype, called Dent’s disease 2. About 25% of Dent’s disease patients do not carry CLCN5/OCRL1 mutations. The CLCN4 and SLC9A6 genes have been investigated, but no mutations have been identified. The recent discovery of a novel mediator of renal amino acid transport, collectrin (the TMEM27 gene), may provide new insight on the pathogenesis of Dent’s disease. We studied 31 patients showing a phenotype resembling Dent’s disease but lacking any CLCN5 mutations by direct sequencing of the OCRL1 and TMEM27 genes. Five novel mutations, L88X, P161HfsX167, F270S, D506N and E720D, in the OCRL1 gene, which have not previously been reported in patients with Dent’s or Lowe disease, were identified among 11 patients with the classical Dent’s disease phenotype. No TMEM27 gene mutations were discovered among 26 patients, 20 of whom had an incomplete Dent’s disease phenotype. Our findings confirm that OCRL1 is involved in the functional defects characteristic of Dent’s disease and suggest that patients carrying missense mutations in exons where many Lowe mutations are mapped may represent a phenotypic variant of Lowe syndrome.

Keywords

Dent’s disease 2 Genotype-phenotype correlation Lowe syndrome OCRL1 mutations TMEM27 gene 

References

  1. 1.
    Frymoyer PA, Scheinman SJ, Dunham PB, Jones B, Hueber P, Schroeder ET (1991) X-linked recessive nephrolithiasis with renal failure. N Engl J Med 325:681–686PubMedCrossRefGoogle Scholar
  2. 2.
    Wrong O, 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. QJM 87:473–493PubMedGoogle Scholar
  3. 3.
    Scheinman SJ, Thakker RV (2000) Genetic aspects of osteoporosis and metabolic bone disease. Humana Press, Totowa, pp 133–152CrossRefGoogle Scholar
  4. 4.
    Lloyd SE, Pearce SHS, 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 379:445–449PubMedCrossRefGoogle Scholar
  5. 5.
    Piwon N, Gunther W, Schwake M, Bösl MR, Jentsch TJ (2000) ClC-5 Cl-channel disruption impairs endocytosis in a mouse model for Dent’s disease. Nature 408:369–373PubMedCrossRefGoogle Scholar
  6. 6.
    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 9:2937–2945PubMedCrossRefGoogle Scholar
  7. 7.
    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 52:911–916PubMedCrossRefGoogle Scholar
  8. 8.
    Ludwig M, Doroszewicz J, Seyberth HW, Bökenkamp A, Balluch B, Nuutinen M, Utsch B, Waldegger S (2005) Functional evaluation of Dentșs disease-causing mutations: implications for ClC-5 channel trafficking and internalization. Hum Genet 117:228–237PubMedCrossRefGoogle Scholar
  9. 9.
    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 65:1615–1620PubMedCrossRefGoogle Scholar
  10. 10.
    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 76:260–267PubMedCrossRefGoogle Scholar
  11. 11.
    Nussbaum RL, Orrison BM, Jänne PA, Charnas L, Chinault AC (1997) Physical mapping and genomic structure of the Lowe syndrome gene OCRL1. Hum Genet 99:145–150PubMedCrossRefGoogle Scholar
  12. 12.
    Lowe CU, Terrey M, MacLachan EA (1952) Organic aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation: a clinical entity. Am J Dis Child 83:164–184Google Scholar
  13. 13.
    Cho HY, Lee BH, Choi HJ, Ha IS, Choi Y, Cheong HI (2008) Renal manifestations of dent disease and lowe syndrome. Pediatr Nephrol 23:243–249PubMedCrossRefGoogle Scholar
  14. 14.
    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 21:2452–2463PubMedCrossRefGoogle Scholar
  15. 15.
    Danilczyk U, Sarao R, Remy C, Benabbas C, Stange G, Richter A, Arya S, Pospisilik JA, Singer D, Camargo SM, Makrides V, Ramadan T, Verrey F, Wagner CA, Penninger JM (2006) Essential role for collectrin in renal amino acid transport. Nature 444:1088–1091PubMedCrossRefGoogle Scholar
  16. 16.
    Mount DB (2007) Collectrin and the kidney. Curr Opin Nephrol Hypertens 16:427–429PubMedCrossRefGoogle Scholar
  17. 17.
    Malakauskas SM, Quan H, Fields TA, McCall SJ, Yu MJ, Kourany WM, Frey CW, Le TH (2007) Aminoaciduria and altered renal expression of luminal amino acid transporters in mice lacking novel gene collectrin. Am J Physiol Renal Physiol 292:F533–F544PubMedCrossRefGoogle Scholar
  18. 18.
    Addis M, Loi M, Lepiani C, Cau M, Melis MA (2004) OCRL mutation analysis in Italian patients with Lowe syndrome. Hum Mutat 23:524–525PubMedCrossRefGoogle Scholar
  19. 19.
    Utsch B, Bokenkamp 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(942):e1–e14PubMedGoogle Scholar
  20. 20.
    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 22:975–980PubMedCrossRefGoogle Scholar
  21. 21.
    Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814PubMedCrossRefGoogle Scholar
  22. 22.
    Ramensky V, Bork P, Sunyaev S (2002) Human non-synonymous SNPs: server and survey. Nucleic Acids Res 30:3894–3900PubMedCrossRefGoogle Scholar
  23. 23.
    Sunyaev S, Ramensky V, Bork P (2000) Towards a structural basis of human non-synonymous single nucleotide polymorphisms. Trends Genet 16:198–200PubMedCrossRefGoogle Scholar
  24. 24.
    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 16:3467–3479PubMedCrossRefGoogle Scholar
  25. 25.
    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 U S A 101:13501–13506PubMedCrossRefGoogle Scholar
  26. 26.
    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 25:3750–3761PubMedCrossRefGoogle Scholar
  27. 27.
    Faucherre A, Desbois P, Satre V, Lunardi J, Dorseuil O, Gacon G (2003) Lowe syndrome protein OCRL1 interacts with Rac GTPase in the trans-Golgi network. Hum Mol Genet 12:2449–2456PubMedCrossRefGoogle Scholar
  28. 28.
    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 13:377–390PubMedCrossRefGoogle Scholar
  29. 29.
    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 369:493–499PubMedCrossRefGoogle Scholar
  30. 30.
    Schneider JF, Boltshauser E, Neuhaus TJ, Rauscher C, Martin E (2001) MRI and proton spectroscopy in Lowe syndrome. Neuropediatrics 32:45–48PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2009

Authors and Affiliations

  • Enrica Tosetto
    • 1
  • Maria Addis
    • 2
  • Gianluca Caridi
    • 3
  • Cristiana Meloni
    • 2
  • Francesco Emma
    • 4
  • Gianluca Vergine
    • 4
  • Gilda Stringini
    • 4
  • Teresa Papalia
    • 5
  • Giancarlo Barbano
    • 3
  • Gian Marco Ghiggeri
    • 3
  • Laura Ruggeri
    • 6
  • Nunzia Miglietti
    • 6
  • Angela D′Angelo
    • 1
  • Maria Antonietta Melis
    • 2
  • Franca Anglani
    • 1
  1. 1.Division of Nephrology, Department of Medical and Surgical SciencesUniversity of PaduaPadovaItaly
  2. 2.Department of Biomedical Sciences and BiotechnologyUniversity of CagliariCagliariItaly
  3. 3.G. Gaslini Pediatric InstituteGenoaItaly
  4. 4.Division of Nephrology and DialysisBambin Gesù Pediatric HospitalRomeItaly
  5. 5.Department of Nephrology‘Annunziata’ HospitalCosenzaItaly
  6. 6.Department of PediatricsUniversity of BresciaBresciaItaly

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