Skip to main content
SpringerLink
Log in

Genetic cause of X-linked Alport syndrome in a family of domestic dogs

  • Original Contributions
  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

Alport syndrome is a hereditary disease of type IV (basement membrane) collagens that occurs spontaneously in humans and dogs. In the human, X-linked Alport syndrome (XLAS) is caused by mutations in COL4A5, resulting in absence of type IV collagen α5 chains from the glomerular basement membrane (GBM) of affected individuals. The consequence of this defect is progressive renal failure, for which the only available treatments are dialysis and transplantation. Recent studies support the prospect of gene transfer therapy for Alport syndrome, but further development of required technologies and demonstration of safety and efficacy must be accomplished in a suitable animal model. We previously identified and have propagated a family of mixed-breed dogs with an inherited nephropathy that exhibits the clinical, immunohistochemical, pathological, and ultrastructural features of human XLAS. To identify the causative mutation, COL4A5 cDNAs from normal and affected dogs were sequenced in their entirety. Sequence analyses revealed a 10-bp deletion in exon 9 of affected dogs. This deletion causes a frame-shift that results in a premature stop codon in exon 10. Characterization of the causative mutation was followed by development of an allele-specific test for identification of dogs in this kindred that are destined to develop XLAS.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Barker DF, Hostikka SL, Zhou J, Chow LT, Oliphant AR et al. (1990) Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 248, 1224–1226

    Article  PubMed  CAS  Google Scholar 

  2. Bernard MA, Valli VE (1977) Familial renal disease in Samoyed dogs. Can Vet J 18, 181–189

    PubMed  CAS  Google Scholar 

  3. Boye E, Mollet G, Forestier L, Cohen-Solal L, Heidet L et al. (1998) Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome. Am J Hum Genet 63, 1329–1340

    Article  PubMed  CAS  Google Scholar 

  4. Cosgrove D, Meehan DT, Grunkemeyer JA, Kornak JM, Sayers R et al. (1996) Collagen COL4A3 knockout: a mouse model for autosomal Alport syndrome. Genes Dev 10, 2981–2992

    Article  PubMed  CAS  Google Scholar 

  5. Gross O, Netzer K-O, Lambrecht R, Seibold S, Weber M (2002) Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counseling. Nephrol Dial Transplant 17, 1218–1227

    Article  PubMed  Google Scholar 

  6. Gunwar S, Ballester F, Noelken ME, Sado Y, Ninomiya Y et al. (1998) Glomerular basement membrane; identification of a novel disulfide-cross-linked network of α3, α4, and α5 chains of type IV collagen and its implications for the pathogenesis of Alport syndrome. J Biol Chem 273, 8767–8775

    Article  PubMed  CAS  Google Scholar 

  7. Guo C, Van Damme B, Van Damme-Lombaerts R, Van de Berghe H, Cassiman JJ et al. (1993) Differential splicing of COL4A5 mRNA in kidney and white blood cells: complex mutation in the COL4A5 gene of an Alport patient deletes the NC1 domain. Kidney Int 44, 1316–1321

    Article  PubMed  CAS  Google Scholar 

  8. Harvey SJ, Zheng K, Sado Y, Naito I, Ninomiya Y et al. (1998) Role of distinct type IV collagen networks in glomerular development and function. Kidney Int 54, 1857–1866

    Article  PubMed  CAS  Google Scholar 

  9. Heidet L, Yi C, Guicharnaud L, Antignac C, Gubler MC (2000) Glomerular expression of type IV collagen chains in normal and X-linked Alport syndrome kidneys. Am J Pathol 156, 1901–1910

    PubMed  CAS  Google Scholar 

  10. Heidet L, Arrondel C, Forestier L, Cohen-Solal L, Mollet G et al. (2001) Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. J Am Soc Nephrol 12, 97–106

    PubMed  CAS  Google Scholar 

  11. Hood JC, Savige J, Hendtlass A, Kleppel MM, Huxtable CR et al. (1995) Bull terrier hereditary nephritis: a model for autosomal dominant Alport syndrome. Kidney Int 47, 758–765

    Article  PubMed  CAS  Google Scholar 

  12. Hostikka SL, Eddy RL, Byers MG, Höyhtyä M, Shows TB et al. (1990) Identification of a distinct type IV collagen a chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome. Proc Natl Acad Sci USA 87, 1606–1610

    Article  PubMed  CAS  Google Scholar 

  13. Hudson BG, Reeders ST, Tryggvason K (1993) Type IV collagen: structure, gene organization, and role in human diseases. J Biol Chem 268, 26033–26036

    PubMed  CAS  Google Scholar 

  14. Inoue Y, Nishio H, Shirakawa T, Nakanishi K, Nakamura H et al. (1999) Detection of mutations in the COL4A5 gene in over 90% of male patients with X-linked Alport’s syndrome by RT-PCR and direct sequencing. Am J Kid Dis 34, 854–862

    Article  PubMed  CAS  Google Scholar 

  15. Jais JP, Knebelmann B, Giatras I, de Marchi M, Rizzoni G et al. (2000) X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in males. J Am Soc Nephrol 11, 649–657

    PubMed  CAS  Google Scholar 

  16. Jansen B, Thorner PS, Singh A, Patterson JM, Lumsden JH et al. (1984) Hereditary nephritis in Samoyed dogs. Am J Pathol 116, 175–178

    PubMed  CAS  Google Scholar 

  17. Kalluri R, Shield CF, Todd P, Hudson BG, Neilson EG (1997) Isoform switching of type IV collagen is developmentally arrested in X-linked Alport syndrome leading to increased susceptibility of renal basement membranes to endoproteolysis. J Clin Invest 99, 2470–2478

    Article  PubMed  CAS  Google Scholar 

  18. Kashtan CE (1998) Disease of the month: Alport syndrome and thin glomerular basement membrane disease. J Am Soc Nephrol 9, 1736–1750

    PubMed  CAS  Google Scholar 

  19. Kashtan CE (2002) Animal models of Alport syndrome. Nephrol Dial Transplant 17, 1359–1361

    Article  PubMed  Google Scholar 

  20. Knebelmann B, Breillat C, Forestier L, Arrondel C, Jacassier D et al. (1996) Spectrum of mutations in the COL4A5 collagen gene in X-linked Alport syndrome. Am J Hum Genet 59, 1221–1232

    PubMed  CAS  Google Scholar 

  21. Lees GE, Helman RG, Kashtan CE, Michael AF, Homco LD et al. (1998) A model of autosomal recessive Alport syndrome in English cocker spaniel dogs. Kidney Int 54, 706–719

    Article  PubMed  CAS  Google Scholar 

  22. Lees GE, Helman RG, Kashtan CE, Michael AF, Homco LD et al. (1999) New form of X-linked dominant hereditary nephritis in dogs. Am J Vet Res 60, 373–383

    PubMed  CAS  Google Scholar 

  23. Lemmink HH, Mochizuki T, van den Heuvel LPWJ, Schroder CH, Barrientos A et al. (1994) Mutations in the type IV collagen α3 [COL4A3] gene in autosomal recessive Alport syndrome. Hum Mol Genet 3, 1269–1273

    Article  PubMed  CAS  Google Scholar 

  24. Levy M, Feingold J (2000) Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int 58, 925–943

    Article  PubMed  CAS  Google Scholar 

  25. Loirat C, Ehrich JHH, Geerlings W, Jones EHP, Landais P et al. (1994) Report on management of renal failure in children in Europe, XXIII, 1992. Nephrol Dial Transplant, Suppl. 1, 26–40

    Google Scholar 

  26. Longo I, Porcedda P, Mari F, Giachino D, Meloni I et al. (2002) COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int 61, 1947–1956

    Article  PubMed  CAS  Google Scholar 

  27. Lu W, Phillips CL, Killen PD, Hlaing T, Harrison WR et al. (1999) Insertional mutation of the collagen genes COL4A3 and COL4A4 and in a mouse model of Alport syndrome. Genomics 61, 113–124

    Article  PubMed  CAS  Google Scholar 

  28. Martin P, Heiskari N, Zhou J, Leinonen A, Tumelius T et al. (1998) High mutation detection rate in the COL4A5 collagen gene in suspected Alport syndrome using PCR and direct DNA sequencing. J Am Soc Nephrol 9, 2291–2301

    PubMed  CAS  Google Scholar 

  29. Martin PH, Tryggvason K (2001) Two novel alternatively spliced 9 bp exons in the COL4A5 gene. Pediatr Nephrol 16, 41–44

    Article  PubMed  CAS  Google Scholar 

  30. Miner JH (1999) Perespectives in basic science: renal basement membrane components. Kidney Int 56, 2016–2024

    Article  PubMed  CAS  Google Scholar 

  31. Miner JH, Sanes JR (1996) Molecular and functional defects in kidneys of mice lacking collagen α3(IV): implications for Alport syndrome. J Cell Biol 135, 1403–1413

    Article  PubMed  CAS  Google Scholar 

  32. Mochizuki T, Lemmink HH, Mariyama M, Antignac C, Gubler MC et al. (1994) Identification of mutations in the alpha-3(IV) and alpha-4(IV) collagen genes in autosomal recessive Alport syndrome. Nat Genet 8, 77–82

    Article  PubMed  CAS  Google Scholar 

  33. Nakanishi K, Yoshikawa N, Iijima K, Kitagawa K, Nakamura H et al. (1994) Immunohistochemical study of α-5 chains of type IV collagen in hereditary nephritis. Kidney Int 46, 1413–1421

    Article  PubMed  CAS  Google Scholar 

  34. Pajari H, Kääriäinen H, Muhonen T, Koskimies O (1996) Alport’s syndrome in 78 patients: Epidemiological and clinical study. Acta Paediatr 85, 1300–1306

    Article  PubMed  CAS  Google Scholar 

  35. Pihlajaniemi T, Pohjolainen ER, Myers JC (1990) Complete primary structure of the triple-helical region and the carboxyl-terminal domain of a new type IV collagen chain, α(IV). J Biol Chem 265, 13758–3766

    PubMed  CAS  Google Scholar 

  36. Tryggvason K, Martin P (2001) Alport syndrome and basement membrane collagen, chap. 214 In: The Metabolic and Molecular Basis of Inherited Disease, 8th ed. Shriver CR, Beaudet AL, Sly WS, Valle D, Childs B et al. (Philadelphia: McGraw-Hill), pp 5453–5466

    Google Scholar 

  37. United States Renal Data System: Incidence and prevalence of ESRD (1996) Am J Kid Dis 28 (Suppl. 2), S34-S47

    Google Scholar 

  38. Zheng K, Thorner PS, Marrano P, Baumal R, McInnes RR (1994) Canine X chromosome-linked hereditary nephritis: a genetic model for human X-linked hereditary nephritis resulting from a single base mutation in the gene encoding the α5 chain of collagen type IV. Proc Natl Acad Sci USA 91, 3989–3993

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathobiology, College of Veterinary Medicine, Texas A&M University, 77843-4467, College Station, TX, USA

    Melissa L. Cox & Keith E. Murphy

  2. Program in Genetics, Texas A&M University, 77843, College Station, Texas, USA

    Melissa L. Cox & Keith E. Murphy

  3. Department of Small Animal Medicine and Surgery, Texas A&M University, 77843, College Station, Texas, USA

    George E. Lees

  4. Department of Pediatrics, University of Minnesota Medical School, 55455, Minneapolis, Minnesota, USA

    Clifford E. Kashtan

Authors
  1. Melissa L. Cox
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. George E. Lees
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Clifford E. Kashtan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Keith E. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Keith E. Murphy.

Additional information

The sequence determined during the course of this work has been deposited in GenBank. The Accession number is AF470624.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cox, M.L., Lees, G.E., Kashtan, C.E. et al. Genetic cause of X-linked Alport syndrome in a family of domestic dogs. Mammalian Genome 14, 396–403 (2003). https://doi.org/10.1007/s00335-002-2253-9

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-002-2253-9

Keywords

Search

Navigation