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. 1994 Apr 26;91(9):3989–3993. doi: 10.1073/pnas.91.9.3989

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 alpha 5 chain of collagen type IV.

K Zheng 1, P S Thorner 1, P Marrano 1, R Baumal 1, R R McInnes 1
PMCID: PMC43708  PMID: 8171024

Abstract

Many families with X-chromosome linked hereditary nephritis (HN) have mutations in the gene on the X chromosome that codes for the alpha 5 chain of collagen type IV. Canine X-linked HN is an animal model for human X-linked HN. To study the alpha 5(IV) gene in this model, we used the nucleotide sequence published for the human alpha 5(IV) cDNA to construct sets of primers covering approximately 95% of the complete cDNA. cDNA from both affected and normal dog kidneys was amplified by PCR in nine overlapping regions. The nucleotide sequence encoding the noncollagenous domain NC1 hybridized to the human X chromosome and was 93% identical at the DNA level and 97% identical at the protein level to the human alpha 5(IV) NC1 domain, confirming that the canine alpha 5(IV) cDNA had been amplified. Sequence analysis of the alpha 5(IV) cDNA detected a single nucleotide substitution, G-->T, in affected dogs, changing a codon for a conserved glycine residue (GGA) to a stop codon (TGA). When genomic DNA was amplified, the same abnormality was found in exon 35. Using the canine NC1 domain cDNA as a probe for Northern analysis, two transcripts of approximately 8.6 kb and approximately 6.7 kb were identified in both normal and affected male dog kidney RNA. However, the abundance of both transcripts was decreased by a factor of approximately 10 in the affected dog. These results establish at the molecular level that canine X-linked HN is a model for human X-linked HN. This model provides an opportunity to determine the efficacy of new therapies and to investigate the role of the alpha 5(IV) chain in type IV collagen assembly.

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Selected References

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

  1. Atkin C. L., Hasstedt S. J., Menlove L., Cannon L., Kirschner N., Schwartz C., Nguyen K., Skolnick M. Mapping of Alport syndrome to the long arm of the X chromosome. Am J Hum Genet. 1988 Feb;42(2):249–255. [PMC free article] [PubMed] [Google Scholar]
  2. Baumal R., Thorner P., Valli V. E., McInnes R., Marrano P., Jacobs R., Binnington A., Bloedow A. G. Renal disease in carrier female dogs with X-linked hereditary nephritis. Implications for female patients with this disease. Am J Pathol. 1991 Oct;139(4):751–764. [PMC free article] [PubMed] [Google Scholar]
  3. Brunner H., Schröder C., van Bennekom C., Lambermon E., Tuerlings J., Menzel D., Olbing H., Monnens L., Wieringa B., Ropers H. H. Localization of the gene for X-linked Alport's syndrome. Kidney Int. 1988 Oct;34(4):507–510. doi: 10.1038/ki.1988.210. [DOI] [PubMed] [Google Scholar]
  4. Butkowski R. J., Langeveld J. P., Wieslander J., Hamilton J., Hudson B. G. Localization of the Goodpasture epitope to a novel chain of basement membrane collagen. J Biol Chem. 1987 Jun 5;262(16):7874–7877. [PubMed] [Google Scholar]
  5. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  6. Emanuel B. S., Sellinger B. T., Gudas L. J., Myers J. C. Localization of the human procollagen alpha 1(IV) gene to chromosome 13q34 by in situ hybridization. Am J Hum Genet. 1986 Jan;38(1):38–44. [PMC free article] [PubMed] [Google Scholar]
  7. Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
  8. Feingold J., Bois E., Chompret A., Broyer M., Gubler M. C., Grünfeld J. P. Genetic heterogeneity of Alport syndrome. Kidney Int. 1985 Apr;27(4):672–677. doi: 10.1038/ki.1985.63. [DOI] [PubMed] [Google Scholar]
  9. Glisin V., Crkvenjakov R., Byus C. Ribonucleic acid isolated by cesium chloride centrifugation. Biochemistry. 1974 Jun 4;13(12):2633–2637. doi: 10.1021/bi00709a025. [DOI] [PubMed] [Google Scholar]
  10. Griffin C. A., Emanuel B. S., Hansen J. R., Cavenee W. K., Myers J. C. Human collagen genes encoding basement membrane alpha 1 (IV) and alpha 2 (IV) chains map to the distal long arm of chromosome 13. Proc Natl Acad Sci U S A. 1987 Jan;84(2):512–516. doi: 10.1073/pnas.84.2.512. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Grünfeld J. P. The clinical spectrum of hereditary nephritis. Kidney Int. 1985 Jan;27(1):83–92. doi: 10.1038/ki.1985.14. [DOI] [PubMed] [Google Scholar]
  12. Gunwar S., Saus J., Noelken M. E., Hudson B. G. Glomerular basement membrane. Identification of a fourth chain, alpha 4, of type IV collagen. J Biol Chem. 1990 Apr 5;265(10):5466–5469. [PubMed] [Google Scholar]
  13. Habib R., Gubler M. C., Hinglais N., Noël L. H., Droz D., Levy M., Mahieu P., Foidart J. M., Perrin D., Bois E. Alport's syndrome: experience at Hôpital Necker. Kidney Int Suppl. 1982 May;11:S20–S28. [PubMed] [Google Scholar]
  14. Hostikka S. L., Eddy R. L., Byers M. G., Höyhtyä M., Shows T. B., Tryggvason K. Identification of a distinct type IV collagen alpha chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1606–1610. doi: 10.1073/pnas.87.4.1606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hudson B. G., Wieslander J., Wisdom B. J., Jr, Noelken M. E. Goodpasture syndrome: molecular architecture and function of basement membrane antigen. Lab Invest. 1989 Sep;61(3):256–269. [PubMed] [Google Scholar]
  16. Jansen B., Thorner P., Baumal R., Valli V., Maxie M. G., Singh A. Samoyed hereditary glomerulopathy (SHG). Evolution of splitting of glomerular capillary basement membranes. Am J Pathol. 1986 Dec;125(3):536–545. [PMC free article] [PubMed] [Google Scholar]
  17. Jansen B., Tryphonas L., Wong J., Thorner P., Maxie M. G., Valli V. E., Baumal R., Basrur P. K. Mode of inheritance of Samoyed hereditary glomerulopathy: an animal model for hereditary nephritis in humans. J Lab Clin Med. 1986 Jun;107(6):551–555. [PubMed] [Google Scholar]
  18. Johansson C., Butkowski R., Wieslander J. The structural organization of type IV collagen. Identification of three NC1 populations in the glomerular basement membrane. J Biol Chem. 1992 Dec 5;267(34):24533–24537. [PubMed] [Google Scholar]
  19. Kashtan C., Fish A. J., Kleppel M., Yoshioka K., Michael A. F. Nephritogenic antigen determinants in epidermal and renal basement membranes of kindreds with Alport-type familial nephritis. J Clin Invest. 1986 Oct;78(4):1035–1044. doi: 10.1172/JCI112658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kleppel M. M., Fan W., Cheong H. I., Michael A. F. Evidence for separate networks of classical and novel basement membrane collagen. Characterization of alpha 3(IV)-alport antigen heterodimer. J Biol Chem. 1992 Feb 25;267(6):4137–4142. [PubMed] [Google Scholar]
  21. Kleppel M. M., Kashtan C. E., Butkowski R. J., Fish A. J., Michael A. F. Alport familial nephritis. Absence of 28 kilodalton non-collagenous monomers of type IV collagen in glomerular basement membrane. J Clin Invest. 1987 Jul;80(1):263–266. doi: 10.1172/JCI113057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kleppel M. M., Kashtan C., Santi P. A., Wieslander J., Michael A. F. Distribution of familial nephritis antigen in normal tissue and renal basement membranes of patients with homozygous and heterozygous Alport familial nephritis. Relationship of familial nephritis and Goodpasture antigens to novel collagen chains and type IV collagen. Lab Invest. 1989 Sep;61(3):278–289. [PubMed] [Google Scholar]
  23. Kohaut E. C., Singer D. B., Nevels B. K., Hill L. L. The specificity of split renal membranes in hereditary nephritis. Arch Pathol Lab Med. 1976 Sep;100(9):475–479. [PubMed] [Google Scholar]
  24. Langeveld J. P., Wieslander J., Timoneda J., McKinney P., Butkowski R. J., Wisdom B. J., Jr, Hudson B. G. Structural heterogeneity of the noncollagenous domain of basement membrane collagen. J Biol Chem. 1988 Jul 25;263(21):10481–10488. [PubMed] [Google Scholar]
  25. Mariyama M., Kalluri R., Hudson B. G., Reeders S. T. The alpha 4(IV) chain of basement membrane collagen. Isolation of cDNAs encoding bovine alpha 4(IV) and comparison with other type IV collagens. J Biol Chem. 1992 Jan 15;267(2):1253–1258. [PubMed] [Google Scholar]
  26. Myers J. C., Jones T. A., Pohjolainen E. R., Kadri A. S., Goddard A. D., Sheer D., Solomon E., Pihlajaniemi T. Molecular cloning of alpha 5(IV) collagen and assignment of the gene to the region of the X chromosome containing the Alport syndrome locus. Am J Hum Genet. 1990 Jun;46(6):1024–1033. [PMC free article] [PubMed] [Google Scholar]
  27. Pihlajaniemi T., Pohjolainen E. R., Myers J. C. Complete primary structure of the triple-helical region and the carboxyl-terminal domain of a new type IV collagen chain, alpha 5(IV). J Biol Chem. 1990 Aug 15;265(23):13758–13766. [PubMed] [Google Scholar]
  28. Reeders S. T. Molecular genetics of hereditary nephritis. Kidney Int. 1992 Sep;42(3):783–792. doi: 10.1038/ki.1992.348. [DOI] [PubMed] [Google Scholar]
  29. Saus J., Wieslander J., Langeveld J. P., Quinones S., Hudson B. G. Identification of the Goodpasture antigen as the alpha 3(IV) chain of collagen IV. J Biol Chem. 1988 Sep 15;263(26):13374–13380. [PubMed] [Google Scholar]
  30. Savage C. O., Noel L. H., Crutcher E., Price S. R., Grunfeld J. P., Lockwood C. M. Hereditary nephritis: immunoblotting studies of the glomerular basement membrane. Lab Invest. 1989 May;60(5):613–618. [PubMed] [Google Scholar]
  31. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  32. Spear G. S., Slusser R. J. Alport's syndrome. Emphasizing electron microscopic studies of the glomerulus. Am J Pathol. 1972 Nov;69(2):213–224. [PMC free article] [PubMed] [Google Scholar]
  33. Thorner P., Baumal R., Valli V. E., Mahuran D., McInnes R., Marrano P. Abnormalities in the NC1 domain of collagen type IV in GBM in canine hereditary nephritis. Kidney Int. 1989 Mar;35(3):843–850. doi: 10.1038/ki.1989.62. [DOI] [PubMed] [Google Scholar]
  34. Thorner P., Jansen B., Baumal R., Valli V. E., Goldberger A. Samoyed hereditary glomerulopathy. Immunohistochemical staining of basement membranes of kidney for laminin, collagen type IV, fibronectin, and Goodpasture antigen, and correlation with electron microscopy of glomerular capillary basement membranes. Lab Invest. 1987 Apr;56(4):435–443. [PubMed] [Google Scholar]
  35. Tryggvason K., Zhou J., Hostikka S. L., Shows T. B. Molecular genetics of Alport syndrome. Kidney Int. 1993 Jan;43(1):38–44. doi: 10.1038/ki.1993.8. [DOI] [PubMed] [Google Scholar]
  36. Tsilibary E. C., Charonis A. S. The role of the main noncollagenous domain (NC1) in type IV collagen self-assembly. J Cell Biol. 1986 Dec;103(6 Pt 1):2467–2473. doi: 10.1083/jcb.103.6.2467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Zhou J., Hertz J. M., Leinonen A., Tryggvason K. Complete amino acid sequence of the human alpha 5 (IV) collagen chain and identification of a single-base mutation in exon 23 converting glycine 521 in the collagenous domain to cysteine in an Alport syndrome patient. J Biol Chem. 1992 Jun 25;267(18):12475–12481. [PubMed] [Google Scholar]
  38. Zhou J., Hostikka S. L., Chow L. T., Tryggvason K. Characterization of the 3' half of the human type IV collagen alpha 5 gene that is affected in the Alport syndrome. Genomics. 1991 Jan;9(1):1–9. doi: 10.1016/0888-7543(91)90214-y. [DOI] [PubMed] [Google Scholar]
  39. Zhou J., Mochizuki T., Smeets H., Antignac C., Laurila P., de Paepe A., Tryggvason K., Reeders S. T. Deletion of the paired alpha 5(IV) and alpha 6(IV) collagen genes in inherited smooth muscle tumors. Science. 1993 Aug 27;261(5125):1167–1169. doi: 10.1126/science.8356449. [DOI] [PubMed] [Google Scholar]

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