The clinical investigator

, Volume 70, Issue 9, pp 809–815 | Cite as

Molecular aspects of Alport's syndrome

  • M. Weber
  • K. -O. Netzer
  • O. Pullig
Guest Lecture, “Gesellschaft für Nephrologie”, 23rd Congress


We review the recent progress achieved on the understanding of the molecular basis of Alport's syndrome. This inherited disease is defined as progressive nephritis with sensorineural hearing loss. In 80%–85% of the families, inheritance is compatible with X-linked dominant transmission, whereas in the remaining cases autosomal dominant transmission is assumed. Histology studies demonstrated that the main defect is within the glomerular basement membrane (GBM). In addition, evidence for an altered GBM antigenicity came from immunofluorescence studies which showed a reduced or absent binding of anti-GBM autoantibodies or monoclonal antibodies to the “Goodpasture antigen” in some families. Subsequent studies added substantial evidence that Alport's syndrome is a type IV collagen disease. Genetic linkage analyses coherently identified an Alport locus at the X-chromosomal region Xg21.3–22. Recently, a previously unknown α5 chain of type IV collagen was identified, and the corresponding gene was also mapped to Xg22. Subsequent studies on Alport families by various groups identified more than 25 COL4A5 lesions. Segregation in linkage with the Alport phenotype could be shown in large kindreds. Mainly deletions and only a few point mutations were described. Most lesions reported so far are heterogeneous. We were able to identify two deletions and one point mutation involving a 3′ splice site in 20 Alport families from Germany. One of the patients with a COL4A5 deletion and the patient with the splice site mutation developed anti-GBM antibodies after renal transplantation. In contrast, no COL4A5 lesions have been found in 2 further patients with posttransplant anti-GBM nephritis. The posttransplant anti-GBM antibodies mainly react with the NC domain of the α3(IV) chain, which has been shown to carry the target epitopes of Goodpasture autoantibodies. The results are discussed comprehensively.

Key words

Alport COL4A5 Anti-GBM antibodies Inherited diseases 



glomerular basement membrane


Alport's syndrome


polymerise chain reaction


denaturing gradient gel electrophoresis


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  1. 1.
    Alport AC (1927) Hereditary congenital haemorrhagic nephritis. Br Med J 1: 504–506.CrossRefGoogle Scholar
  2. 2.
    Antignac C, Dechênes G, Gros F, Knebelmann B, Tryggvason K, Gubler MC (1991) Mutations in COL4A5 gene in Alport syndrome (abstract). J Am Soc Nephrol 2:249.Google Scholar
  3. 3.
    Atkin CL, Gregory MC, Border WA (1988) Alport syndrome. In: Schrier RW, Gottschalk CW (eds) Diseases of the kidney, Vol 1. Little, Brown & Company, Boston, pp 617–641.Google Scholar
  4. 4.
    Barker DF, Hostikka SL, Zhou J, Chow LT, Oliphant AR, Gerken SC, Gregory MC, Skolnick MH, Atkin CL, Tryggvason K (1990) Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 248:1224–1227.CrossRefGoogle Scholar
  5. 5.
    Brunner H, Schröder C, Bennekom C van, Lambermon E, Tuerlings J, Menzel D, Olbing H, Monnens L, Wieringa B, Ropers HH (1988) Localization of the gene for X-linked Alport's syndrome. Kidney Int 34:507–510.CrossRefGoogle Scholar
  6. 6.
    Butkowski RJ, Wieslander J, Wisdom BJ, Barr JF, Noelken ME, Hudson BJ (1985) Properties of the globular domain of type IV collagen and its relationship to the Goodpasture antigen. J Biol Chem 260:3739–3747.PubMedGoogle Scholar
  7. 7.
    Feingold J, Bois E, Chompret A, Broyer M, Gubler MC, Grünfeld JP (1985) Genetic heterogeneity of Alport syndrome. Kidney Int 27:672–677.CrossRefGoogle Scholar
  8. 8.
    Flinter FA, Abbs S, Bobrow M (1989) Localization of the gene for classic Alport syndrome. Genomics 4:335–338.CrossRefGoogle Scholar
  9. 9.
    Gregory MC, Skinner B, Atkin CL, Barker DF (1991) A novel mutation in COL4A5 relates three families with type IV Alport syndrome (abstract). J Am Soc Nephrol 2:254.Google Scholar
  10. 10.
    Griffin Ca, Emanuel BS, Hansen JR, Cavenee WK, Myers JC (1987) Human collagen genes encoding basement membrane α1(IV) and α2(IV) chains map to the distal long arm of chromosome 13. Proc Natl Acad Sci USA 84:512–516.CrossRefGoogle Scholar
  11. 11.
    Gunwar S, Ballester F, Kalluri R, Timoneda J, Chonko AM, Esward SJ, Noelken ME, Hudson BG (1991) Glomerular basement membrane. J Biol Chem 266:15318–15319.PubMedGoogle Scholar
  12. 12.
    Hasstedt SJ, Atkin CL, San Juan AC (1986) Genetic heterogeneity among kindreds with Alport syndrome. Am J Hum Genet 38:940–953.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Higuchi M, Kazazian HH Jr, Kasch L, Warren TC, McGinniss MJ, Phillips JA III, Kasper C, Janco R, Antonarakis SE (1991) Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci USA 88:7405–7409.CrossRefGoogle Scholar
  14. 14.
    Higuchi M, Antonarakis SE, Kasch L, Oldenburg J, Economou-Petersen E, Olek K, Arai M, Inabe H, Kazazian HH (1991) Molecular characterization of mild to moderate hemophilia A: detection of the mutation in 25 of 29 patients by denaturating gradient gel electrophoresis. Proc Natl Acad Sci USA 88:8307–8311.CrossRefGoogle Scholar
  15. 15.
    Hostikka SL, Eddy RL, Byer MG, Höyhtya M, Shows TB, Tryggvason K (1990) Identification of a distinct type IV collagen α 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.CrossRefGoogle Scholar
  16. 16.
    Hudson BJ, Wieslander J, Wisdom BJ, Noelken ME (1989) Goodpasture syndrome: molecular architecture and function of basement membrane antigen. Lab Invest 61:256–269.PubMedGoogle Scholar
  17. 17.
    Hudson BJ, Kalluri R, Gunwar S, Weber M, Ballester F, Hudson J, Noelken ME, Sarras M, Richardson WR, Saus J, Abrahamson R, Glick AD, Haralson MA, Helderman JH, Stone J, Jacobson HR (1992) The pathogenesis of Alport syndrome involves type IV collagen molecules containing the α3(IV) chain: evidence from anti-glomerular basement membrane nephritis after renal transplantation. Kidney Int (in press).Google Scholar
  18. 18.
    Jackson RJ, Standart N (1990) Do the poly (A) tail and 3′ untranslated region control mRNA translation? Cell 62:15–24.CrossRefGoogle Scholar
  19. 19.
    Jenis EH, Valeski JE, Calcagno PL (1981) Variability of anti-GBM binding in hereditary nephritis. Clin Nephrol 15:111–114.PubMedGoogle Scholar
  20. 20.
    Kashtan C, Fish AJ, Kleppel M, Yoshioka K, Michael AF (1986) Nephritogenic antigen determinants in epidermal and renal basement membranes of kindreds with Alport-type familial nephritis. J Clin Invest 78:1035–1044.CrossRefGoogle Scholar
  21. 21.
    Kashtan CE, Kleppel MM, Butkowski RJ, Michael AF, Fish AJ (1990) Alport syndrome, basement membranes and collagen. Pediatr Nephrol 4:523–532.CrossRefGoogle Scholar
  22. 22.
    Kashtan CE, Rich SS, Michael AF, De Martinville B (1990) Gene mapping in Alport families with different basement membrane antigenic phenotypes. Kidney Int 38:925–930.CrossRefGoogle Scholar
  23. 23.
    Kashtan CE, Michael AF, Kleppel MM (1991) Alport syndrome: association of deletions in the COL4A5 gene with post-transplant anti-GBM nephritis (abstract). J Am Soc Nephrol 2:256.Google Scholar
  24. 24.
    Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC (1989) Identification of the cystic fibrosis gene: genetic analysis. Science 245:1073–1080.CrossRefGoogle Scholar
  25. 25.
    Kleppel M, Michael AF, Fish AJ (1986) Antibody specificity of human glomerular basement membrane type IV collagen NC1 subunits. J Biol Chem 261:16547–16552.PubMedGoogle Scholar
  26. 26.
    Kleppel MM, Kashtan CE, Butkowski RJ, Fish AJ, Michael AF (1987) Alport familial nephritis. J Clin Invest 80: 263–266.CrossRefGoogle Scholar
  27. 27.
    Kleppel MM, Kashtan C, Sand PA, Wieslander J, Michael AJ (1989) Distribution of familial nephritis antigen in normal tissue and renal basement membranes of patients with homozygous and heterozygous Alport familial nephritis. Lab Invest 61:278–289.PubMedGoogle Scholar
  28. 28.
    Koenig M, Hoffmann EP, Bertelson CJ, Monaco AP, Feener C, Kunkel CM (1987) Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 50:509–517.CrossRefGoogle Scholar
  29. 29.
    Mariyama M, Kalluri R, Hudson BJ, Reeders ST (1992) The α4(IV) chain of basement membrane collagen: isolation of cDNA's encoding bovine α4(IV) and comparison with other type IV collagens. J Biol Chem (manuscript submitted).Google Scholar
  30. 30.
    McCoy RC, Johnson HK, Stone WJ, Wilson CB (1982) Absence of nephritogenic GBM antigen(s) in some patients with hereditary nephritis. Kidney Int 21:642–652.CrossRefGoogle Scholar
  31. 31.
    Morrison KE, Mariyama M, Yang-Feng TL, Reeders ST (1991) Sequence and localization of a partial cDNA encoding the human α3 chain of type IV collagen. Am J Hum Genet 49: 545–554.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Myers JC, Jones TA, Pohjolainen ER, Kadri AS, Goddard AD, Sheer D, Solomon E, Pihlajaniemi T (1990) Molecular cloning of α5(IV) collagen and assignment of the gene to the region of the X chromosome containing the Alport syndrome locus. Am J Hum Genet 46:1024–1033.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Netzer K-O, Renders L, Pullig O, Tryggvason K, Weber M (1991) Mutations in the COL4A5 gene in X-linked Alport syndrome (abstract). J Am Soc Nephrol 2:257.Google Scholar
  34. 34.
    Netzer K-O, Renders L, Zhou J, Pullig O, Tryggvason K, Weber M (1992) Deletions of the COL4A5 gene in patients with Alport syndrome. Kidney Int (in press).Google Scholar
  35. 35.
    Netzer K-O, Pullig O, Tryggvason K, Frei U, Weber M: Detection of a COL4A5 splice site mutation and analysis of the α5(IV) collagen mRNA isolated from peripheral blood lymphocytes in a patient with Alport syndrome. (manuscript submitted).Google Scholar
  36. 36.
    Noel LH, Gubler MC, Bobri G, Savage COS, Lockwood CM, Grünfeld JP (1989) Inherited diseases of renal basement membrane. Adv Nephrol 18:77–94.Google Scholar
  37. 37.
    Olson DL, Anand SK, Landig BH, Heuser E, Grushkin CM, Liebermann E (1980) Diagnosis of hereditary nephritis by failure of glomeruli to bind anti-glomerular basement membrane antibodies. Pediatrics 96:697–699.CrossRefGoogle Scholar
  38. 38.
    Pihlajaniemi T, Pohjolainen ER, Myers CM (1990) Complete primary structure of the triple-helical region and the carboxyl terminal domain of a new type IV collagen chain, α5(IV). J Biol Chem 265:13758–13766.PubMedGoogle Scholar
  39. 39.
    Pochet JM, Bobrie G, Landais P, Goldfarb B, Grünfeld JP (1989) Renal prognosis in Alport's and related-syndromes: influence of the mode of inheritance. Nephrol Dial Transplant 4:1016–1021.PubMedGoogle Scholar
  40. 40.
    Pullig O, Netzer KO, Tryggvason K, Weber M (1991) Analysis of COL4A5 gene and of anti-GBM antibody reactivity in Alport syndrome (AS) patients with anti-GBM disease after renal transplantation (abstract). J Am See Nephrol 2:258.Google Scholar
  41. 41.
    Roberts RG, Bentley DR, Barby TFM, Manners E, Borbrow M (1990) Direct diagnosis of carriers of Duchenne and Becker muscular dystrophy by amplification of lymphocyte RNA. Lancet 336:1523–1526.CrossRefGoogle Scholar
  42. 42.
    Rumpelt HJ (1987) Alport's syndrome: specificity and pathogenesis of glomerular basement membrane alterations. Pediatr Nephrol 1:422–427.CrossRefGoogle Scholar
  43. 43.
    Rumpelt HJ, Steinke A, Thoenes W (1992) Alport-type glomerulopathy: evidence for diminished capillary loop size. Clin Nephrol 37:54–64.Google Scholar
  44. 44.
    Saus W, Wieslander J, Langeveld JP, Quinones S, Hudson BG (1988) Identification of the Goodpasture antigen as the α3(IV) chain of collagen IV. J Biol Chem 263:13374–13380.PubMedGoogle Scholar
  45. 45.
    Savage COS, Reed A, Kershaw M, Pincott J, Pusey CD, Dillon MJ, Barratt TM, Lockwood CM (1986) Use of monoclonal antibody in differential diagnosis of children with haematuria and hereditary nephritis. Lancet I:1459–1461.CrossRefGoogle Scholar
  46. 46.
    Savage COS, Noel LH, Crutcher E, Price SR, Grünfeld JP, Lockwood CM (1989) Hereditary nephritis: immunoblotting studies of the glomerular basement membrane. Lab Invest 60:613–618.PubMedGoogle Scholar
  47. 47.
    Szpiro-Tapia S, Bobrie G, Guilloud-Bataille M, Heuertz S, Julier C, Frezal J, Grünfeld JP, Hors-Cayla MC (1988) Linkae studies in X-linked Alport's syndrome. Hum Genet 81:85–87.CrossRefGoogle Scholar
  48. 48.
    Weber M (1992) Basement membrane proteins. Kidney Int 41:620–628.CrossRefGoogle Scholar
  49. 49.
    Weber M, Pullig O (1992) Different immunologic properties of the globular NC1 domain of collagen type IV isolated from various human basement membranes. Eur J Clin Invest 22:138–146.CrossRefGoogle Scholar
  50. 50.
    Weber M, Manns M, Meyer zum Büschenfelde K-H, Köhler H (1988) Dot-immunobinding assay with the globular domain of collagen type IV for antiglomerular basement membrane antibodies. J Clin Lab Anal 2:199–204.CrossRefGoogle Scholar
  51. 51.
    Weber M, Meyer zum Büschenfelde K-H, Köhler H (1988) Immunological properties of the human Goodpasture target antigen. Clin Exp Immunol 74:289–294.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Wieslander J, Barr JF, Butkowski RJ, Edwards SJ, Bygren P, Heinegard D, Hudson BG (1984) Goodpasture antigen of the glomerular basement membrane: localization to noncollagenous regions of type IV collagen. Proc Natl Acad Sci USA 81:3838–3842.CrossRefGoogle Scholar
  53. 53.
    Yoshikawa N, Cameron AH, White RHR (1981) The glomerular basal lamina in hereditary nephritis. J Pathol 135:199–209.CrossRefGoogle Scholar
  54. 54.
    Zhou J, Barker DF, Hostikka SL, Gregory MC, Atkin CL, Tryggvason K (1991) Single base mutation in α5(IV) collagen chain gene converting a conserved cysteine to serine in Alport syndrome. Genomics 9:10–18.CrossRefGoogle Scholar
  55. 55.
    Zhou J, Hostikka SL, Chow LT, Tryggvason K (1991) Characterization of the 3′ half of the human type IV collagen α5 gene that is affected in the Alport syndrome. Genomics 9:1–9.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • M. Weber
    • 1
  • K. -O. Netzer
    • 1
  • O. Pullig
    • 1
  1. 1.Medizinische Klinik IV mit PoliklinikUniversität Erlangen-NürnbergErlangenGermany

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