Skip to main content
PMC home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2002 Dec;39(12):882–892. doi: 10.1136/jmg.39.12.882

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

T Hart 1, M Gorry 1, P Hart 1, A Woodard 1, Z Shihabi 1, J Sandhu 1, B Shirts 1, L Xu 1, H Zhu 1, M Barmada 1, A Bleyer 1
PMCID: PMC1757206  PMID: 12471200

Abstract

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 (597.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antonarakis S. E. Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum Mutat. 1998;11(1):1–3. doi: 10.1002/(SICI)1098-1004(1998)11:1<1::AID-HUMU1>3.0.CO;2-O. [DOI] [PubMed] [Google Scholar]
  2. Benson G. Tandem repeats finder: a program to analyze DNA sequences. Nucleic Acids Res. 1999 Jan 15;27(2):573–580. doi: 10.1093/nar/27.2.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bross P., Corydon T. J., Andresen B. S., Jørgensen M. M., Bolund L., Gregersen N. Protein misfolding and degradation in genetic diseases. Hum Mutat. 1999;14(3):186–198. doi: 10.1002/(SICI)1098-1004(1999)14:3<186::AID-HUMU2>3.0.CO;2-J. [DOI] [PubMed] [Google Scholar]
  4. Cameron J. S., Moro F., Simmonds H. A. Gout, uric acid and purine metabolism in paediatric nephrology. Pediatr Nephrol. 1993 Feb;7(1):105–118. doi: 10.1007/BF00861588. [DOI] [PubMed] [Google Scholar]
  5. Chen W. C., Lin H. S., Chen H. Y., Shih C. H., Li C. W. Effects of Tamm-Horsfall protein and albumin on calcium oxalate crystallization and importance of sialic acids. Mol Urol. 2001 Spring;5(1):1–5. doi: 10.1089/109153601750124186. [DOI] [PubMed] [Google Scholar]
  6. Chen W. C., Lin H. S., Tsai F. J., Li C. W. Effects of Tamm-Horsfall protein and albumin on the inhibition of free radicals. Urol Int. 2001;67(4):305–309. doi: 10.1159/000051008. [DOI] [PubMed] [Google Scholar]
  7. Cockcroft D. W., Gault M. H. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41. doi: 10.1159/000180580. [DOI] [PubMed] [Google Scholar]
  8. Dahan K., Fuchshuber A., Adamis S., Smaers M., Kroiss S., Loute G., Cosyns J. P., 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. doi: 10.1681/ASN.V12112348. [DOI] [PubMed] [Google Scholar]
  9. 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. doi: 10.1111/j.1365-2362.1988.tb01171.x. [DOI] [PubMed] [Google Scholar]
  10. Flagiello L., Cirigliano V., Strazzullo M., Cappa V., Ciccodicola A., D'Esposito M., Torrente I., Werner R., Di Iorio G., Rinaldi M. 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] [Google Scholar]
  11. Fletcher A. P., Neuberger A., Ratcliffe W. A. Tamm-Horsfall urinary glycoprotein. The subunit structure. Biochem J. 1970 Nov;120(2):425–432. doi: 10.1042/bj1200425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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] [Google Scholar]
  13. 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 Feb 26;70(4):943–954. doi: 10.1086/339689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hateboer N., Gumbs C., Teare M. D., Coles G. A., Griffiths D., Ravine D., Futreal P. A., Rahman N. Confirmation of a gene locus for medullary cystic kidney disease (MCKD2) on chromosome 16p12. Kidney Int. 2001 Oct;60(4):1233–1239. doi: 10.1046/j.1523-1755.2001.00932.x. [DOI] [PubMed] [Google Scholar]
  15. Hession C., Decker J. M., Sherblom A. P., Kumar S., Yue C. C., Mattaliano R. J., Tizard R., Kawashima E., Schmeissner U., Heletky S. Uromodulin (Tamm-Horsfall glycoprotein): a renal ligand for lymphokines. Science. 1987 Sep 18;237(4821):1479–1484. doi: 10.1126/science.3498215. [DOI] [PubMed] [Google Scholar]
  16. Hoyer J. R., Sisson S. P., Vernier R. L. Tamm-Horsfall glycoprotein: ultrastructural immunoperoxidase localization in rat kidney. Lab Invest. 1979 Aug;41(2):168–173. [PubMed] [Google Scholar]
  17. Huang Z. Q., Sanders P. W. 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. doi: 10.1172/JCI119218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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. doi: 10.1038/ncb802. [DOI] [PubMed] [Google Scholar]
  19. Kahn A. M. Effect of diuretics on the renal handling of urate. Semin Nephrol. 1988 Sep;8(3):305–314. [PubMed] [Google Scholar]
  20. 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. doi: 10.1002/1529-0131(200004)43:4<925::AID-ANR26>3.0.CO;2-B. [DOI] [PubMed] [Google Scholar]
  21. Kelly C. J., Neilson E. G. Medullary cystic disease: an inherited form of autoimmune interstitial nephritis? Am J Kidney Dis. 1987 Nov;10(5):389–395. doi: 10.1016/s0272-6386(87)80108-7. [DOI] [PubMed] [Google Scholar]
  22. MIKKELSEN W. M., DODGE H. J., VALKENBURG H. THE DISTRIBUTION OF SERUM URIC ACID VALUES IN A POPULATION UNSELECTED AS TO GOUT OR HYPERURICEMIA: TECUMSEH, MICHIGAN 1959-1960. Am J Med. 1965 Aug;39:242–251. doi: 10.1016/0002-9343(65)90048-3. [DOI] [PubMed] [Google Scholar]
  23. Massari P. U., Hsu C. H., Barnes R. V., Fox I. H., Gikas P. W., Weller J. M. Familial hyperuricemia and renal disease. Arch Intern Med. 1980 May;140(5):680–684. [PubMed] [Google Scholar]
  24. Muchmore A. V., Decker J. M. Uromodulin: a unique 85-kilodalton immunosuppressive glycoprotein isolated from urine of pregnant women. Science. 1985 Aug 2;229(4712):479–481. doi: 10.1126/science.2409603. [DOI] [PubMed] [Google Scholar]
  25. O'Connell J. R., Weeks D. E. The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recoding and fuzzy inheritance. Nat Genet. 1995 Dec;11(4):402–408. doi: 10.1038/ng1295-402. [DOI] [PubMed] [Google Scholar]
  26. Pace J. M., Atkinson M., Willing M. C., Wallis G., Byers P. H. 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. doi: 10.1002/humu.1193. [DOI] [PubMed] [Google Scholar]
  27. Pennica D., Kohr W. J., Kuang W. J., Glaister D., Aggarwal B. B., Chen E. Y., Goeddel D. V. Identification of human uromodulin as the Tamm-Horsfall urinary glycoprotein. Science. 1987 Apr 3;236(4797):83–88. doi: 10.1126/science.3453112. [DOI] [PubMed] [Google Scholar]
  28. Pirulli D., Puzzer D., De Fusco M., Crovella S., Amoroso A., Scolari F., Viola B. F., Maiorca R., Caridi G., Savoldi S. 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] [Google Scholar]
  29. Resnick J. S., Sisson S., Vernier R. L. Tamm-Horsfall protein. Abnormal localization in renal disease. Lab Invest. 1978 May;38(5):550–555. [PubMed] [Google Scholar]
  30. Rieselbach R. E., Steele T. H. Intrinsic renal disease leading to abnormal urate excretion. Nephron. 1975;14(1):81–87. doi: 10.1159/000180437. [DOI] [PubMed] [Google Scholar]
  31. 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. doi: 10.1002/humu.10113. [DOI] [PubMed] [Google Scholar]
  32. 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. doi: 10.1016/s0378-1119(02)00725-4. [DOI] [PubMed] [Google Scholar]
  33. 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. doi: 10.1051/vetres:2002018. [DOI] [PubMed] [Google Scholar]
  34. Scolari F., Puzzer D., Amoroso A., Caridi G., Ghiggeri G. M., 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. doi: 10.1086/302414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sherblom A. P., Decker J. M., Muchmore A. V. The lectin-like interaction between recombinant tumor necrosis factor and uromodulin. J Biol Chem. 1988 Apr 15;263(11):5418–5424. [PubMed] [Google Scholar]
  36. 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 Apr 25;66(6):1989–1994. doi: 10.1086/302936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. TAMM I., HORSFALL F. L., 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] [Google Scholar]
  38. Terrinoni A., Smith F. J., Didona B., Canzona F., Paradisi M., Huber M., Hohl D., David A., Verloes A., Leigh I. M. 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. doi: 10.1046/j.0022-202x.2001.01565.x. [DOI] [PubMed] [Google Scholar]
  39. Thompson G. R., Weiss J. J., Goldman R. T., Rigg G. A. Familial occurrence of hyperuricemia, gout, and medullary cystic disease. Arch Intern Med. 1978 Nov;138(11):1614–1617. [PubMed] [Google Scholar]
  40. 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. doi: 10.1002/humu.10092. [DOI] [PubMed] [Google Scholar]
  41. Wilcox W. D. Abnormal serum uric acid levels in children. J Pediatr. 1996 Jun;128(6):731–741. doi: 10.1016/s0022-3476(96)70322-0. [DOI] [PubMed] [Google Scholar]
  42. Zager R. A., Cotran R. S., Hoyer J. R. Pathologic localization of Tamm-Horsfall protein in interstitial deposits in renal disease. Lab Invest. 1978 Jan;38(1):52–57. [PubMed] [Google Scholar]
  43. Zhang Y., Gorry M. C., Hart P. S., Pettenati M. J., Wang L., Marks J. J., Lu X., Hart T. C. 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. doi: 10.1159/000059337. [DOI] [PubMed] [Google Scholar]
  44. 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. doi: 10.1002/1439-7633(20020802)3:8<726::AID-CBIC726>3.0.CO;2-C. [DOI] [PubMed] [Google Scholar]
  45. den Dunnen J. T., Antonarakis S. E. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat. 2000;15(1):7–12. doi: 10.1002/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]

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

RESOURCES