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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

Summary

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 

Abbreviations

GBM

glomerular basement membrane

AS

Alport's syndrome

PCR

polymerise chain reaction

DGGE

denaturing gradient gel electrophoresis

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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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