Skip to main content

Advertisement

SpringerLink
Log in

Medullary cystic kidney disease type 1: mutational analysis in 37 genes based on haplotype sharing

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Medullary cystic kidney disease type 1 (MCKD1) is an autosomal dominant, tubulo-interstitial nephropathy that causes renal salt wasting and end-stage renal failure in the fourth to seventh decade of life. MCKD1 was localized to chromosome 1q21. We demonstrated haplotype sharing and confirmed the telomeric border by a recombination of D1S2624 in a Belgian kindred. Since the causative gene has been elusive, high resolution haplotype analysis was performed in 16 kindreds. Clinical data and blood samples of 257 individuals (including 75 affected individuals) from 26 different kindreds were collected. Within the defined critical region mutational analysis of 37 genes (374 exons) in 23 MCKD1 patients was performed. In addition, for nine kindreds RT-PCR analysis for the sequenced genes was done to screen for mutations activating cryptic splice sites. We found consistency with the haplotype sharing hypothesis in an additional nine kindreds, detecting three different haplotype subsets shared within a region of 1.19 Mb. Mutational analysis of all 37 positional candidate genes revealed sequence variations in 3 different genes, AK000210, CCT3, and SCAMP3, that were segregating in each affected kindred and were not found in 96 healthy individuals, indicating, that a single responsible gene causing MCKD1 remains elusive. This may point to involvement of different genes within the MCKD1 critical region.

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

Similar content being viewed by others

References

  • Auranen M, Ala-Mello S, Turunen JA, Jarvela I (2001) Further evidence for linkage of autosomal-dominant medullary cystic kidney disease on chromosme 1q21. Kidney Int 60:1225–1232

    Article  PubMed  CAS  Google Scholar 

  • Bell AW, Ward MA, Blackstock WP, Freeman HN, Choudhary JS, Lewis AP, Chotai D, Fazel A, Gushue JN, Paiement J, Palcy S, Chevet E, Lafreniere-Roula M, Solari R, Thomas DY, Rowley A, Bergeron JJ (2001) Proteomics characterization of abundant Golgi membrane proteins. J Biol Chem 276:5152–5165

    Article  PubMed  CAS  Google Scholar 

  • Camasses A, Bogdanova A, Shevchenko A, Zachariae W (2003) The CCT chaperonin promotes activation of the anaphase-promoting complex through the generation of functional Cdc20. Mol Cell 12:87–100

    Article  PubMed  CAS  Google Scholar 

  • Christodoulou K, Tsingis M, Stavrou C, Eleftheriou A, Papapavlou P, Patsalis PC, Ioannou P, Pierides A, Constantinou Deltas C (1998) Chromosome 1 localization of a gene for autosomal dominant medullary cystic kidney disease. Hum Mol Genet 7:905–911

    Article  PubMed  CAS  Google Scholar 

  • Cohn DH, Shohat T, Yahav M, Ilan T, Rechavi G, King L, Shohat M (2000) A Locus for an autosomal dominant form of progressive renal failure and hypertension at chromosme 1q21. Am J Hum Genet 67:647–651

    Article  PubMed  CAS  Google Scholar 

  • Dahan K, Devuyst O, Smaers M, Vertommen D, Loute G, Poux JM, Viron B, Jacquot C, Gagnadoux MF, Chauveau D, Buchler M, Cochat P, Cosyns JP, 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  PubMed  CAS  Google Scholar 

  • Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293–298

    Article  PubMed  CAS  Google Scholar 

  • Fernandez-Chacon R, Sudhof TC (2000) Novel SCAMPs lacking NPF repeats: ubiquitous and synaptic vesicle-specific forms implicate SCAMPs in multiple membrane-trafficking functions. J Neurosci 20:7941–7950

    PubMed  CAS  Google Scholar 

  • Fuchshuber A, Kroiss S, Karle S, Berthold S, Huck K, Burton C, Rahman N, Koptides M, Deltas C, Otto E, Ruschendorf F, Feest T, Hildebrandt F (2001) Refinement of the gene locus for autosomal dominant medullary cystic kidney disease type 1 (MCKD1) and construction of a physical and partial transcriptional map of the region. Genomics 72:278–284

    Article  PubMed  CAS  Google Scholar 

  • Gardner KD Jr (1971) Evolution of clinical signs in adult-onset cystic disease of the renal medulla. Ann Intern Med 74:47–54

    PubMed  Google Scholar 

  • 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  PubMed  CAS  Google Scholar 

  • Hildebrandt F, Otto E, Rensing C, Nothwang HG, Vollmer M, Adolphs J, Hanusch H, Brandis M (1997) A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat Genet 17:149–153

    Article  PubMed  CAS  Google Scholar 

  • Hildebrandt F, Otto E (2000) Molecular genetics of nephronophthisis and medullary cystic kidney disease. J Am Soc Nephrol 11:1753–1761

    PubMed  CAS  Google Scholar 

  • Hirotsune S, Yoshida N, Chen A, Garrett L, Sugiyama F, Takahashi S, Yagami K, Wynshaw-Boris A, Yoshiki A (2003) An expressed pseudogene regulates the messenger-RNA stability of its homologous coding gene. Nature 423:91–96

    Article  PubMed  CAS  Google Scholar 

  • http://bioinformatics.weizmann.ac.il/cards/. Cited 10 Nov 2004

  • http://genome.ucsc.edu/. Cited 10 Nov 2004

  • http://www.ensembl.org/. Cited 10 Nov 2004

  • http://www.ncbi.nlm.nih.gov/. Cited 13 Nov 2004

  • http://www.ncbi.nlm.nih.gov/BLAST/. Cited 10 Nov 2004

  • http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Gene. Cited 10 Feb 2004

  • http://zeon.well.ox.ac.uk/git-bin/primer3. Cited between Jan 2004 and Aug 2004

  • Huan Y, van Adelsberg J (1999) Polycystin-1, the PKD1 gene product, is in a complex containing E-cadherin and the catenins. J Clin Invest 104:1459–1468

    Article  PubMed  CAS  Google Scholar 

  • Hugo C (2003) The thrombospondin 1-TGF-beta axis in fibrotic renal disease. Nephrol Dial Transplant 18:1241–1245

    Article  PubMed  CAS  Google Scholar 

  • Kiser RL, Wolf MT, Martin JL, Zalewski I, Attanasio M, Hildebrandt F, Klemmer P (2004) Medullary cystic kidney disease type 1 in a large native American kindred. Am J Kidney Dis 44:611–617

    Article  PubMed  CAS  Google Scholar 

  • Lammerding J, Schulze PC, Takahashi T, Kozlov S, Sullivan T, Kamm RD, Stewart CL, Lee RT (2004) Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J Clin Invest 113:370–378

    PubMed  CAS  Google Scholar 

  • Leeker A, Kreft B, Sandmann J, Bates J, Wasenauer G, Muller H, Sack K, Kumar S (1997) Tamm-Horsfall protein inhibits binding of S- and P-fimbriated Escherichia coli to human renal tubular epithelial cells. Exp Nephrol 5:38–46

    PubMed  CAS  Google Scholar 

  • Llorca O, Martin-Benito J, Gomez-Puertas P, Ritco-Vonsovici M, Willison KR, Carrascosa JL, Valpuesta JM (2001) Analysis of the interaction between the eukaryotic chaperonin CCT and its substrates actin and tubulin. J Struct Biol 135:205–218

    Article  PubMed  CAS  Google Scholar 

  • Marengo SR, Chen DH, Kaung HL, Resnick MI, Yang L (2002) Decreased renal expression of the putative calcium oxalate inhibitor Tamm-Horsfall protein in the ethylene glycol rat model of calcium oxalate urolithiasis. J Urol 167:2192–2197

    Article  PubMed  CAS  Google Scholar 

  • Nurnberger J, Bacallao RL, Phillips CL (2002) Inversin forms a complex with catenins and N-cadherin in polarized epithelial cells. Mol Biol Cell 13:3096–3106

    Article  PubMed  CAS  Google Scholar 

  • Olbrich H, Fliegauf M, Hoefele J, Kispert A, Otto E, Volz A, Wolf MT, Sasmaz G, Trauer U, Reinhardt R, Sudbrak R, Antignac C, Gretz N, Walz G, Schermer B, Benzing T, Hildebrandt F, Omran H (2003) Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Nat Genet 34:455–459

    Article  PubMed  CAS  Google Scholar 

  • Otto E, Hoefele J, Ruf R, Mueller AM, Hiller KS, Wolf MT, Schuermann MJ, Becker A, Birkenhager R, Sudbrak R, Hennies HC, Nurnberg P, Hildebrandt F (2002) A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution. Am J Hum Genet 71:1161–1167

    Article  PubMed  CAS  Google Scholar 

  • Otto EA, Schermer B, Obara T, O’Toole JF, Hiller KS, Mueller AM, Ruf RG, Hoefele J, Beekmann F, Landau D, Foreman JW, Goodship JA, Strachan T, Kispert A, Wolf MT, Gagnadoux MF, Nivet H, Antignac C, Walz G, Drummond IA, Benzing T, Hildebrandt F (2003) Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat Genet 34:413–420

    Article  PubMed  CAS  Google Scholar 

  • Otto EA, Loeys B, Khanna H, Hellemans J, Sudbrak R, Fan S, Muerb U, O’Toole JF, Helou J, Attanasio M, Utsch B, Sayer JA, Lillo C, Jimeno D, Coucke P, De Paepe A, Reinhardt R, Klages S, Tsuda M, Kawakami I, Kusakabe T, Omran H, Imm A, Tippens M, Raymond PA, Hill J, Beales P, He S, Kispert A, Margolis B, Williams DS, Swaroop A, Hildebrandt F (2005) Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet 37:282–288

    Article  PubMed  CAS  Google Scholar 

  • Rampoldi L, Caridi G, Santon D, Boaretto F, Bernascone I, Lamorte G, Tardanico R, Dagnino M, Colussi G, Scolari F, Ghiggeri GM, Amoroso A, Casari G (2003) Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics. Hum Mol Genet 12:3369–3384

    Article  PubMed  CAS  Google Scholar 

  • Rhodes DCJ (2002) Binding of Tamm–Horsfall protein to complement 1q and complement 1, including influence of hydrogen-ion concentration. Immunol Cell Biol 78:558–566

    Article  Google Scholar 

  • Sariola H, Holm K, Henke-Fahle S (1988) Early innervation of the metanephric kidney. Development 104:589–599

    PubMed  CAS  Google Scholar 

  • Scolari F, Puzzer D, Amoroso A, Caridi G, Ghiggeri GM, Maiorca R, Aridon P, De Fusco M, Ballabio A, Casari G (1999) Identification of a new locus for medullary cystic disease, on chromosome 16p12. Am J Hum Genet 64:1655–1660

    Article  PubMed  CAS  Google Scholar 

  • de Silva DC, Wheatley DN, Herriot R, Brown T, Stevenson DA, Helms P, Dean JC (1997) Mulvihill-Smith progeria-like syndrome: a further report with delineation of phenotype, immunologic deficits, and novel observation of fibroblast abnormalities. Am J Med Genet 69:56–64

    Article  PubMed  Google Scholar 

  • Sobel E, Lange K (1996) Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet 58:1323–1337

    PubMed  CAS  Google Scholar 

  • Stavrou C, Koptides M, Tombazos C, Psara E, Patsias C, Zouvani I, Kyriacou K, Hildebrandt F, Christofides T, Pierides A, Deltas CC (2002) Autosomal-dominant medullary cystic kidney disease type1: clinical and molecular findings in six large Cypriot families. Kidney Int 62:1385–1394

    Article  PubMed  Google Scholar 

  • Ying WZ, Sanders PW (2001) Mapping the binding domain of immunoglobulin light chains for Tamm–Horsfall protein. Am J Pathol 158:1859–1866

    PubMed  CAS  Google Scholar 

  • Yoder BK, Hou X, Guay-Woodford LM (2002) The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol 13:2508–2516

    Article  PubMed  CAS  Google Scholar 

  • Vos HL, Devarayalu S, de Vries Y, Bornstein P (1992) Thrombospondin 3 (Thbs3), a new member of the thrombospondin gene family. J Biol Chem 267:12192–12196

    PubMed  CAS  Google Scholar 

  • Waldherr R, Lennert T, Weber HP, Fodisch HJ, Scharer K (1982) The nephronophthisis complex: a clinicopathologic study in children. Virchows Arch 394:235–254

    Article  CAS  Google Scholar 

  • Walkley NA, Demaine AG, Malik AN (1996) Cloning, structure and mRNA expression of human Cctg, which encodes the chaperonin subunit CCT-gamma. Biochem J 313:381–389

    PubMed  CAS  Google Scholar 

  • Watnick T, Germino G (2003) From cilia to cyst. Nat Genet 34:355–356

    Article  PubMed  CAS  Google Scholar 

  • Wilcox WD (1996) Abnormal serum uric acid levels in children. J Pediatr 128:731–741

    Article  PubMed  CAS  Google Scholar 

  • Winfield SL, Tayebi N, Martin BM, Ginns EI, Sidransky E (1997) Identification of three additional genes contiguous to the glucocerebrosidase locus on chromosome 1q21: implications for Gaucher disease. Genome Res 7:1020–1026

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Wolf MT, Mucha BE, Attanasio M, Zalewski I, Karle SM, Neumann HP, Rahman N, Bader B, Baldamus CA, Otto E, Witzgall R, Fuchshuber A, Hildebrandt F (2003b) 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  PubMed  CAS  Google Scholar 

  • Wolf MT, van Vlem B, Hennies HC, Zalewski I, Karle SM, Puetz M, Panther F, Otto E, Fuchshuber A, Lameire N, Loeys B, Hildebrandt F (2004) Telomeric refinement of the MCKD1 locus on chromosome 1q21. Kidney Int 66:580–585 (Editorial pp 864–865)

    Google Scholar 

  • Wu TT, Castle JD (1998) Tyrosine phosphorylation of selected secretory carrier membrane proteins, SCAMP1 and SCAMP3, and association with the EGF receptor. Mol Biol Cell 9:1661–1674

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank all members of the MCKD families for their participation. We are indebted to A. Nayir, B. Loeys, W. Wong, M. Anlauf, P. Klemmer and J. Matyus for contribution of clinical data and blood samples, and R. H. Lyons for excellent large-scale sequencing. The outstanding technical assistance of Anita Imm and Steffi Schneider is gratefully acknowledged. Dr. Fuchshuber and Dr. Hildebrandt were supported by a grant from the German Research Foundation (DFG Fu 202/2-1) and the Fritz-Thyssen-Stiftung (1999–2001). Dr. Wolf was supported by grants from the Koeln Fortune Program Faculty of Medicine, University of Cologne (184/2004) and the German Research Foundation (DFG WO 1229/2-1).

Author information

Authors and Affiliations

  1. Departments of Pediatrics and Human Genetics, University of Michigan, Ann Arbor, MI, USA

    Matthias T. F. Wolf, Bettina E. Mucha, Massimo Attanasio, Franziska Panther, Isabella Zalewski, Edgar A. Otto & Friedhelm Hildebrandt

  2. Max-Delbrueck Center for Molecular Medicine, Berlin-Buch, Germany

    Hans C. Hennies

  3. University Children’s Hospital, Freiburg University, Freiburg, Germany

    Stephanie M. Karle & Arno Fuchshuber

  4. Department of Molecular Genetics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

    C. Constantinou Deltas

  5. University Children’s Hospital, Cologne University, Cologne, Germany

    Matthias T. F. Wolf

  6. Department of Human Genetics, Cologne University, Cologne, Germany

    Matthias T. F. Wolf

  7. Department of Pediatrics and Communicable Diseases, University of Michigan, 8220C MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI, 48109-0646, USA

    Friedhelm Hildebrandt

Authors
  1. Matthias T. F. Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bettina E. Mucha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hans C. Hennies
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Massimo Attanasio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Franziska Panther
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Isabella Zalewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stephanie M. Karle
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Edgar A. Otto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C. Constantinou Deltas
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Arno Fuchshuber
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Friedhelm Hildebrandt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Friedhelm Hildebrandt.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wolf, M.T.F., Mucha, B.E., Hennies, H.C. et al. Medullary cystic kidney disease type 1: mutational analysis in 37 genes based on haplotype sharing. Hum Genet 119, 649–658 (2006). https://doi.org/10.1007/s00439-006-0176-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-006-0176-3

Keywords

Search

Navigation