Abstract
The glomerular and tubular basement membranes are the principal barriers to filtration and re-absorption of water and molecules in the nephron. They are composed primarily of type IV collagen, laminin, fibronectin, sulphated proteoglycans and collagen type I. Three common inherited diseases are associated with abnormalities of basement membrane proteins: Alport's syndrome, thin basement membrane disease (TBMD) and adult polycystic kidney disease. In this review we describe the application of molecular biological techniques to the study of these conditions.
Classic Alport's syndrome is an X-linked disorder with a lamellated glomerular basement membrane (GBM) which typically results in renal failure in males. Studies with sera from patients with Goodpasture's syndrome, or monoclonal antibodies specific for the Goodpasture antigen, show that the Goodpasture antigen is absent or masked in the kidneys of individuals with Alport's syndrome. There is some evidence to suggest that the Goodpasture antigen is best represented by the non-collagenous domain of the alpha 3 chain of type IV collagen, but that other non-collagenous regions may also contribute to the antigen. It is through these non-collagenous regions that the type IV collagen chains form the typical network, and the abnormality in Alport's syndrome interferes with this network formation. However, we have recently demonstrated that the gene for the non-collagenous domain of the alpha 3 collagen chain is present in individuals with Alport's syndrome. Furthermore, other groups have shown a defect in a novel type IV collagen chain, the alpha 5 chain, in 3 unrelated cases of Alport's syndrome. The gene for the alpha 5 chain is present on the long arm of the X chromosome, and is consistent with the usual mode of inheritance in classic Alport's syndrome. The chromosomal localizations of the alpha 3 and 4 chains have not yet been determined.
In thin basement membrane disease the principal abnormality is the attenuated intermediate layer of lamina densa of the GBM but neither the abnormal protein nor the gene defect has yet been determined. We have shown, using restriction fragment length polymorphisms and cDNA corresponding to the alpha 1 and 2 chains of type IV collagen, that these genes are probably not involved.
Adult polycystic kidney disease is associated with reduced proteoglycans in the renal basement membranes but whether this is the primary abnormality is unclear. The abnormal gene has not yet been identified but linkage studies have localized it to the short arm of chromosome 16, and DNA probes are useful in making the diagnosis in family studies. Currently, attempts are being made to pin-point the precise genetic abnormality but this may take several years.