Alport syndrome, basement membranes and collagen

Abstract

Alport syndrome, an inherited disorder of the kidney, eye and ear, has fascinated nephrologists, pathologists, and geneticists for nearly a century. With the recent application of molecular biochemical and genetic techniques, this mysterious disease has begun to yield some of its secrets. Alport syndrome can now be viewed as a generalized disorder of basement membranes that appears to result from mutations in an X-chromosome-encoded basement membrane collagen chain. This chain, along with two other novel collagen chains, is absent from Alport basement membranes, in contrast to the classical chains of collagen IV. Phenotypic heterogeneity in Alport syndrome probably arises from allelic mutations at a single genetic locus. The phenomenon of post-transplant anti-glomerular basement membrane nephritis may be a manifestation of specific mutations at the Alport locus that prevent synthesis of the gene's protein product and the establishment of immunological tolerance.

Association of Alport's syndrome with HLA-DR2 antigen in a group of unrelated patients

“…The occurrence of a posttransplant anti-GBM nephritis in the allograft donated by an HLA-identical sibling (15) corroborates the relevance of the defect in type IV collagen α chain. On the other hand, anti-GBM nephritis occurs in 5 to 10% of males with Alport's syndrome who undergo kidney transplantation.…”

“…The pathogenic anti-GBM antibody reacts both with normal glomerular and epidermal basement membranes, but not with membranes of most Alport's syndrome patients. These anti-GBM antibodies react with the engrafted GBM in a pattern similar to that observed with Goodpasture sera (15). In this context, 75 to 80% of the patients who develop Goodpasture syndrome have also the HLA-DR2 antigen and the HLA-DRB1*15 allele (16,17).…”

Deletions in the COL4A5 collagen gene in X-linked Alport syndrome. Characterization of the pathological transcripts in nonrenal cells and correlation with disease expression.

“…In this study, the immunohistochemical analysis of the GBM distribution of collagen IV chains revealed the absence of the a3 and a4 chain antigens in four patients with COL4A5 deletions. This finding shows for the first time that structural changes in the a5(IV) chain can impair the incorporation of a3 (IV) and a4(IV) chains within the type IV collagen network, a hypothesis proposed by Kashtan et al (42). About 1-5% of transplanted AS male patients develop anti-GBM antibodies leading to severe crescentic glomerulonephritis and subsequent graft loss.…”

“…lacked combination of restriction fragments hybridizing to one or several cDNA probes, suggesting completely intragenic COL4A5 deletions. The patterns of hybridization observed with the different COL4A5 cDNA probes, and with the genomic probes F7 and F8 in patients J.C., S.L., and F.P., as well as PCR amplification of genomic DNA for exons 38,42, and 45 (see Table I for primers' sequences), allowed us to precize to some extent the size of the deletions (Table II and Fig. 2).…”

Possible Association between Keratoconus and Renal Diseases

“…However, the mechanisms by which these mutations result in glomerulosclerosis and renal failure have yet to be established. A mutation at this locus causes widespread basement membrane changes involving the vas spirale (inner ear), Descemet's and Bruch's membranes, lens capsule and the glomeruli basement membrane [14][15][16].…”