Search tips
Search criteria 


Logo of jmedgeneJournal of Medical GeneticsVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
J Med Genet. 2002 December; 39(12): 882–892.
PMCID: PMC1757206

Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy


Introduction: Medullary cystic kidney disease 2 (MCKD2) and familial juvenile hyperuricaemic nephropathy (FJHN) are both autosomal dominant renal diseases characterised by juvenile onset of hyperuricaemia, gout, and progressive renal failure. Clinical features of both conditions vary in presence and severity. Often definitive diagnosis is possible only after significant pathology has occurred. Genetic linkage studies have localised genes for both conditions to overlapping regions of chromosome 16p11-p13. These clinical and genetic findings suggest that these conditions may be allelic.

Aim: To identify the gene and associated mutation(s) responsible for FJHN and MCKD2.

Methods: Two large, multigenerational families segregating FJHN were studied by genetic linkage and haplotype analyses to sublocalise the chromosome 16p FJHN gene locus. To permit refinement of the candidate interval and localisation of candidate genes, an integrated physical and genetic map of the candidate region was developed. DNA sequencing of candidate genes was performed to detect mutations in subjects affected with FJHN (three unrelated families) and MCKD2 (one family).

Results: We identified four novel uromodulin (UMOD) gene mutations that segregate with the disease phenotype in three families with FJHN and in one family with MCKD2.

Conclusion: These data provide the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders. UMOD is a GPI anchored glycoprotein and the most abundant protein in normal urine. We postulate that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible for the clinical changes of interstitial renal disease, polyuria, and hyperuricaemia found in MCKD2 and FJHN.

Full Text

The Full Text of this article is available as a PDF (597K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Thompson GR, Weiss JJ, Goldman RT, Rigg GA. Familial occurrence of hyperuricemia, gout, and medullary cystic disease. Arch Intern Med. 1978 Nov;138(11):1614–1617. [PubMed]
  • Massari PU, Hsu CH, Barnes RV, Fox IH, Gikas PW, Weller JM. Familial hyperuricemia and renal disease. Arch Intern Med. 1980 May;140(5):680–684. [PubMed]
  • Dahan K, Fuchshuber A, Adamis S, Smaers M, Kroiss S, Loute G, Cosyns JP, Hildebrandt F, Verellen-Dumoulin C, Pirson Y. Familial juvenile hyperuricemic nephropathy and autosomal dominant medullary cystic kidney disease type 2: two facets of the same disease? J Am Soc Nephrol. 2001 Nov;12(11):2348–2357. [PubMed]
  • Hateboer N, Gumbs C, Teare MD, Coles GA, Griffiths D, Ravine D, Futreal PA, Rahman N. Confirmation of a gene locus for medullary cystic kidney disease (MCKD2) on chromosome 16p12. Kidney Int. 2001 Oct;60(4):1233–1239. [PubMed]
  • Scolari F, Puzzer D, Amoroso A, Caridi G, Ghiggeri GM, Maiorca R, Aridon P, De Fusco M, Ballabio A, Casari G. Identification of a new locus for medullary cystic disease, on chromosome 16p12. Am J Hum Genet. 1999 Jun;64(6):1655–1660. [PubMed]
  • Kamatani N, Moritani M, Yamanaka H, Takeuchi F, Hosoya T, Itakura M. Localization of a gene for familial juvenile hyperuricemic nephropathy causing underexcretion-type gout to 16p12 by genome-wide linkage analysis of a large family. Arthritis Rheum. 2000 Apr;43(4):925–929. [PubMed]
  • Stibůrková B, Majewski J, Sebesta I, Zhang W, Ott J, Kmoch S. Familial juvenile hyperuricemic nephropathy: localization of the gene on chromosome 16p11.2-and evidence for genetic heterogeneity. Am J Hum Genet. 2000 Jun;66(6):1989–1994. [PubMed]
  • Zager RA, Cotran RS, Hoyer JR. Pathologic localization of Tamm-Horsfall protein in interstitial deposits in renal disease. Lab Invest. 1978 Jan;38(1):52–57. [PubMed]
  • Cameron JS, Moro F, Simmonds HA. Gout, uric acid and purine metabolism in paediatric nephrology. Pediatr Nephrol. 1993 Feb;7(1):105–118. [PubMed]
  • TAMM I, HORSFALL FL., Jr Characterization and separation of an inhibitor of viral hemagglutination present in urine. Proc Soc Exp Biol Med. 1950 May;74(1):106–108. [PubMed]
  • Muchmore AV, Decker JM. Uromodulin: a unique 85-kilodalton immunosuppressive glycoprotein isolated from urine of pregnant women. Science. 1985 Aug 2;229(4712):479–481. [PubMed]
  • Hoyer JR, Sisson SP, Vernier RL. Tamm-Horsfall glycoprotein: ultrastructural immunoperoxidase localization in rat kidney. Lab Invest. 1979 Aug;41(2):168–173. [PubMed]
  • Resnick JS, Sisson S, Vernier RL. Tamm-Horsfall protein. Abnormal localization in renal disease. Lab Invest. 1978 May;38(5):550–555. [PubMed]
  • Sherblom AP, Decker JM, Muchmore AV. The lectin-like interaction between recombinant tumor necrosis factor and uromodulin. J Biol Chem. 1988 Apr 15;263(11):5418–5424. [PubMed]
  • Hession C, Decker JM, Sherblom AP, Kumar S, Yue CC, Mattaliano RJ, Tizard R, Kawashima E, Schmeissner U, Heletky S, et al. Uromodulin (Tamm-Horsfall glycoprotein): a renal ligand for lymphokines. Science. 1987 Sep 18;237(4821):1479–1484. [PubMed]
  • Dulawa J, Jann K, Thomsen M, Rambausek M, Ritz E. Tamm Horsfall glycoprotein interferes with bacterial adherence to human kidney cells. Eur J Clin Invest. 1988 Feb;18(1):87–91. [PubMed]
  • Chen WC, Lin HS, Tsai FJ, Li CW. Effects of Tamm-Horsfall protein and albumin on the inhibition of free radicals. Urol Int. 2001;67(4):305–309. [PubMed]
  • Chen WC, Lin HS, Chen HY, Shih CH, Li CW. Effects of Tamm-Horsfall protein and albumin on calcium oxalate crystallization and importance of sialic acids. Mol Urol. 2001 Spring;5(1):1–5. [PubMed]
  • Schweigert Florian J, Raila Jens, Haebel Sophie. Vitamin A excreted in the urine of canines is associated with a Tamm-Horsfall like protein. Vet Res. 2002 May-Jun;33(3):299–311. [PubMed]
  • Fossati P, Prencipe L, Berti G. Use of 3,5-dichloro-2-hydroxybenzenesulfonic acid/4-aminophenazone chromogenic system in direct enzymic assay of uric acid in serum and urine. Clin Chem. 1980 Feb;26(2):227–231. [PubMed]
  • Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41. [PubMed]
  • Wilcox WD. Abnormal serum uric acid levels in children. J Pediatr. 1996 Jun;128(6):731–741. [PubMed]
  • Rieselbach RE, Steele TH. Intrinsic renal disease leading to abnormal urate excretion. Nephron. 1975;14(1):81–87. [PubMed]
  • Hart Thomas C, Zhang Yingze, Gorry Michael C, Hart P Suzanne, Cooper Margaret, Marazita Mary L, Marks Jared M, Cortelli Jose R, Pallos Debora. A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1. Am J Hum Genet. 2002 Apr;70(4):943–954. [PubMed]
  • O'Connell JR, Weeks DE. The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recoding and fuzzy inheritance. Nat Genet. 1995 Dec;11(4):402–408. [PubMed]
  • Zhang Y, Gorry MC, Hart PS, Pettenati MJ, Wang L, Marks JJ, Lu X, Hart TC. Localization, genomic organization, and alternative transcription of a novel human SAM-dependent methyltransferase gene on chromosome 2p22-->p21. Cytogenet Cell Genet. 2001;95(3-4):146–152. [PubMed]
  • Benson G. Tandem repeats finder: a program to analyze DNA sequences. Nucleic Acids Res. 1999 Jan 15;27(2):573–580. [PMC free article] [PubMed]
  • Pennica D, Kohr WJ, Kuang WJ, Glaister D, Aggarwal BB, Chen EY, Goeddel DV. Identification of human uromodulin as the Tamm-Horsfall urinary glycoprotein. Science. 1987 Apr 3;236(4797):83–88. [PubMed]
  • Antonarakis SE. Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum Mutat. 1998;11(1):1–3. [PubMed]
  • den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat. 2000;15(1):7–12. [PubMed]
  • Pirulli D, Puzzer D, De Fusco M, Crovella S, Amoroso A, Scolari F, Viola BF, Maiorca R, Caridi G, Savoldi S, et al. Molecular analysis of uromodulin and SAH genes, positional candidates for autosomal dominant medullary cystic kidney disease linked to 16p12. J Nephrol. 2001 Sep-Oct;14(5):392–396. [PubMed]
  • Fletcher AP, Neuberger A, Ratcliffe WA. Tamm-Horsfall urinary glycoprotein. The subunit structure. Biochem J. 1970 Nov;120(2):425–432. [PubMed]
  • Jovine Luca, Qi Huayu, Williams Zev, Litscher Eveline, Wassarman Paul M. The ZP domain is a conserved module for polymerization of extracellular proteins. Nat Cell Biol. 2002 Jun;4(6):457–461. [PubMed]
  • de la Mata Isabel, Garcia Jose L, González Carlos, Menéndez Margarita, Cañada Javier, Jiménez-Barbero Jesús, Asensio Juan Luis. The impact of R53C mutation on the three-dimensional structure, stability, and DNA-binding properties of the human Hesx-1 homeodomain. Chembiochem. 2002 Aug 2;3(8):726–740. [PubMed]
  • Wautot Virginie, Vercherat Cécile, Lespinasse James, Chambe Béatrice, Lenoir Gilbert M, Zhang Chang X, Porchet Nicole, Cordier Martine, Béroud Christophe, Calender Alain. Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein. Hum Mutat. 2002 Jul;20(1):35–47. [PubMed]
  • Robinson Peter N, Booms Patrick, Katzke Stefanie, Ladewig Markus, Neumann Luitgard, Palz Monika, Pregla Reinhard, Tiecke Frank, Rosenberg Thomas. Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies. Hum Mutat. 2002 Sep;20(3):153–161. [PubMed]
  • Pace JM, Atkinson M, Willing MC, Wallis G, Byers PH. Deletions and duplications of Gly-Xaa-Yaa triplet repeats in the triple helical domains of type I collagen chains disrupt helix formation and result in several types of osteogenesis imperfecta. Hum Mutat. 2001 Oct;18(4):319–326. [PubMed]
  • Terrinoni A, Smith FJ, Didona B, Canzona F, Paradisi M, Huber M, Hohl D, David A, Verloes A, Leigh IM, et al. Novel and recurrent mutations in the genes encoding keratins K6a, K16 and K17 in 13 cases of pachyonychia congenita. J Invest Dermatol. 2001 Dec;117(6):1391–1396. [PubMed]
  • Bross P, Corydon TJ, Andresen BS, Jørgensen MM, Bolund L, Gregersen N. Protein misfolding and degradation in genetic diseases. Hum Mutat. 1999;14(3):186–198. [PubMed]
  • Huang ZQ, Sanders PW. Localization of a single binding site for immunoglobulin light chains on human Tamm-Horsfall glycoprotein. J Clin Invest. 1997 Feb 15;99(4):732–736. [PMC free article] [PubMed]
  • Kahn AM. Effect of diuretics on the renal handling of urate. Semin Nephrol. 1988 Sep;8(3):305–314. [PubMed]
  • Kelly CJ, Neilson EG. Medullary cystic disease: an inherited form of autoimmune interstitial nephritis? Am J Kidney Dis. 1987 Nov;10(5):389–395. [PubMed]
  • Salowsky Rüdiger, Heiss Nina S, Benner Axel, Wittig Rainer, Poustka Annemarie. Basal transcription activity of the dyskeratosis congenita gene is mediated by Sp1 and Sp3 and a patient mutation in a Sp1 binding site is associated with decreased promoter activity. Gene. 2002 Jun 26;293(1-2):9–19. [PubMed]
  • Flagiello L, Cirigliano V, Strazzullo M, Cappa V, Ciccodicola A, D'Esposito M, Torrente I, Werner R, Di Iorio G, Rinaldi M, et al. Mutation in the nerve-specific 5'non-coding region of Cx32 gene and absence of specific mRNA in a CMTX1 Italian family. Mutations in brief no. 195. Online. Hum Mutat. 1998;12(5):361–361. [PubMed]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group