Skip to main content
SpringerLink
Log in

Childhood course of renal insufficiency in a family with a uromodulin gene mutation

  • Brief Report
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Mutations in the UMOD gene encoding uromodulin (Tamm-Horsfall glycoprotein) result in the autosomal dominant transmission of progressive renal insufficiency and hypo-uricosuric hyperuricemia leading to gout at an early age. The clinical appearance is characterized by renal insufficiency and gout occurring in the late teenage years, with end-stage kidney disease characteristically developing between 40 and 70 years of age. This report provides a long-term characterization of renal functional decline in three children from one family with a novel UMOD mutation (c.891T>G, p.C297W) who received allopurinol and a low protein diet. While renal functional decline is slow in individuals with UMOD mutations, it may appear early in life and be associated with marked hyperuricemia. Anemia was also noted in this family.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Hart TC, Gorry MC, Hart PS, Woodard AS, Shihabi Z, Sandhu J, Shirts B, Xu L, Zhu H, Barmada MM, Bleyer AJ (2002) Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet 39:882–892

    Article  CAS  PubMed  Google Scholar 

  2. Gusmano R, Caridi G, Marini M, Perfumo F, Ghiggeri G, Piaggio G, Ceccherini I, Seri M (2002) Glomerulocystic kidney disease in a family. Nephrol Dial Transplant 17:813–818

    Article  PubMed  Google Scholar 

  3. Lens XM, Banet JF, Outeda P, Barrio-Lucia V (2005) A novel pattern of mutation in uromodulin disorders: Autosomal dominant medullary cystic kidney disease type 2, familial juvenile hyperuricemic nephropathy, and autosomal dominant glomerulocystic kidney disease. Am J Kidney Dis 46:52–57

    Article  CAS  PubMed  Google Scholar 

  4. Turner J, Stacey J, Harding B, Kotanko K, Lhotta J, Puig J, Roberts I, Torres R, Thakker R (2003) Uromodulin mutations cause familial juvenile hyperuricemic nephropathy. J Clin Endocrinol Metab 88:1398–1401

    Article  CAS  PubMed  Google Scholar 

  5. Dahan K, Devuyst O, Smaers M, Vertommen D, Loute G, Poux J-M, Viron B, Jacquot C, Gagnadoux M-F, Chauveau D, Buchler M, Cochat P, Cosyns J-P, Mougenot B, Rider MH, Antignac C, Verellen-Dumoulin C, Pirson Y (2003) A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin. J Am Soc Nephrol 14:2883–2893

    Article  CAS  PubMed  Google Scholar 

  6. Serafini-Cessi F, Malagolini N, Cavallone D (2003) Tamm-Horsfall glycoprotein biology and clinical relevance. Am J Kidney Dis 42:658–676

    Article  CAS  PubMed  Google Scholar 

  7. Malagolini N, Cavallone D, Serafini-Cessi F (1997) Intracellular transport, cell-surface exposure and release of recombinant Tamm-Horsfall glycoprotein. Kidney Int 52:1340–1350

    Article  CAS  PubMed  Google Scholar 

  8. Scolari F, Caridi G, Rampoldi L, Tardanico R, Izzi C, Pirulli D, Amoroso A, Casari G, Ghiggeri GM (2004) Uromodulin storage diseases: clinical aspects and mechanisms. Am J Kidney Dis 44:987–999

    Article  CAS  PubMed  Google Scholar 

  9. Hoyer JR, Sisson SP, Vernier RL (1979) Tamm-Horsfall glycoprotein ultrastructural immunoperoxidase localization in rat kidney. Lab Invest 41:168–173

    CAS  PubMed  Google Scholar 

  10. Raffi HS, Bates JM, Laszik Z, Kumar S (2009) Tamm-Horsfall protein protects against urinary tract infection by proteus mirabilis. J Vasc Surg 181:2332–2338

    Google Scholar 

  11. Hess B (2004) Tamm-Horsfall glycoprotein and calcium nephrolithiasis. Miner Electrolyte Metab 20:393–398

    Google Scholar 

  12. Kottgen A, Glazer NL, Dehghan A, Hwang SJ, Katz R, Li M, Yang Q, Gudnason V, Launer LJ, Harris TB, Smith AV, Arking DE, Astor BC, Boerwinkle E, Ehret GB, Ruczinski I, Scharpf RB, Chen I, deBoer IH, Haritunians T, Lumley T (2009) Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 41:712–717

    Article  CAS  Google Scholar 

  13. Hildebrandt F, Omram H (2001) New insights: nephronophthisis-medullary cystic kidney disease. Pediatr Nephrol 16:168–176

    Article  CAS  PubMed  Google Scholar 

  14. Wolf MTF, Karle SM, Schwarz S, Anlauf M, Anlauf M, Glaeser L, Kroiss S, Burton C, Feest T, Otto E, Fuchshuber A, Hilderbrant F (2003) Refinement of the critical region for MCKD1 by detection of transcontinental haplotype sharing. Kidney Int 64:788–792

    Article  CAS  PubMed  Google Scholar 

  15. Giselson N, Heinegard N, Holmberg C-G, Lindberg L-G, Lindstedt E, Lindstedt G, Schersten B (1970) Renal medullary cystic disease or familial juvenile nephronophthisis: a renal tubular disease. Am J Med 48:174–184

    Article  CAS  PubMed  Google Scholar 

  16. Hildebrandt F, Otto E (2006) Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease? Nat Rev Genet 6:928–940

    Article  Google Scholar 

  17. Wolf MTF, Mucha BE, Attanasio M, Zalewski I, Karle SM, Neumann HPH, Rahman N, Bader B, Baldamus CA, Otto E, Witzgall R, Fuchshuber A, Hildebrandt F (2003) Mutations of the Uromodulin gene in MCKD type 2 patients cluster in exon 4, which encodes three EGF-like domains. Kidney Int 64:1580–1587

    Article  CAS  PubMed  Google Scholar 

  18. Bleyer AJ, Woodard AS, Shihabi Z, Sandhu J, Zhu H, Satko SG, Weller N, Deterding E, McBride D, Gorry MC, Xu L, Ganier D, Hart TC (2003) Clinical characterization of a family with a mutation in the uromodulin (Tamm-Horsfall glycoprotein) gene. Kidney Int 64:36–42

    Article  CAS  PubMed  Google Scholar 

  19. Choi SW, Ryu OH, Choi SJ, Song IS, Bleyer AJ, Hart TC (2005) Mutant Tamm-Horsfall glycoprotein accumulation in the endoplasmic reticulum induces apoptosis that is reversed by colchicine and sodium 4-phenylbutyrate. J Am Soc Nephrol 16:3006–3014

    Article  CAS  PubMed  Google Scholar 

  20. Wolf MTE, Beck BB, Zaucke F, Kunze A, Misselwitz J, Ruley J, Ronda T, Fischer A, Eifinger F, Licht C, Otto E, Hoppe B, Hildebrandt F (2007) The uromodulin C744G mutation causes MCKD2 and FJHN in children and adults and may be due to a possible founder effect. Kidney Int 71:574–581

    Article  CAS  PubMed  Google Scholar 

  21. Yu KH, See LC, Huang YC, Yang CH, Sun JH (2007) Dietary factors associated with hyperuricemia in adults. Semin Arthritis Rheum 37:243–250

    Article  PubMed  Google Scholar 

  22. Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker G (1994) The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 330:877–884

    Article  CAS  PubMed  Google Scholar 

  23. Ruggenenti P, Bettinaglio P, Pinares F, Remuzzi G (2008) Angiotensin converting enzyme insertion/deletion polymorphism and renoprotection in diabetic and nondiabetic nephropathies. Clin J Am Soc Nephrol 3:1511–1525

    Article  PubMed  Google Scholar 

  24. Bleyer AJ, Trachtman H, Sandhu J, Gorry MC, Hart TC (2003) Renal manifestations of a mutation in the uromodulin (Tamm-Horsfall protein) gene. Am J Kidney Dis 42:1–7

    Article  Google Scholar 

  25. Fairbanks L, Cameron J, Venkata-Raman G, Rigden S, Rees L, van’t Hoff W, Mansell M, Pattison J, Goldsmith D, Simmonds H (2002) Early treatment with allopurinol in familial juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease. Q J Med 95:597–607

    CAS  Google Scholar 

  26. Moro F, Simmonds HA, Cameron JS, Ogg CS, Williams GD, McBride MB, Davis PM (1991) Does allopurinol affect the progression of familial juvenile gouty nephropathy? Adv Exp Med Biol 309A:199–202

    CAS  PubMed  Google Scholar 

  27. Bleyer AJ, Hart TC (2003) Familial juvenile hyperuricaemic nephropathy. Q J Med 96:867–868

    CAS  Google Scholar 

  28. Parra E, Gota R, Gamen A, Moros M, Azuara M (1995) Granulomatous interstitial nephritis secondary to allopurinol treatment. Clin Nephrol 43:350

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Victoria Robins, R.N. for her valuable help.

Author information

Authors and Affiliations

  1. Department of Nephrology and Gastroenterology, Heim Pál Children’s Hospital, Budapest, Hungary

    Péter Schäffer, Éva Gombos & Krisztina Meichelbeck

  2. Department of Urology, Heim Pál Children’s Hospital, Budapest, Hungary

    András Kiss

  3. National Human Genome Research Institute, NIH Human Genome Project, Bethesda, MD, USA

    P. Suzanne Hart

  4. Section on Nephrology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA

    Anthony J. Bleyer

Authors
  1. Péter Schäffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Éva Gombos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Krisztina Meichelbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. András Kiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. Suzanne Hart
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anthony J. Bleyer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anthony J. Bleyer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schäffer, P., Gombos, É., Meichelbeck, K. et al. Childhood course of renal insufficiency in a family with a uromodulin gene mutation. Pediatr Nephrol 25, 1355–1360 (2010). https://doi.org/10.1007/s00467-009-1436-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-009-1436-y

Keywords

Search

Navigation