A COL4A3 GENE MUTATION AND POSTTRANSPLANT ANTI-ALPHA-3(IV) COLLAGEN ALLOANTIBODIES IN ALPORT SYNDROME

The X-linked Alport syndrome is associated with mutations and deletion s in COLA AS gene, one of six genes which constitute the alpha-chains of type IV collagen in basement membranes. The autosomal recessive for m of Alport syndrome is characterized by mutations and deletions in th e COL4A3 and COL4A4 genes. A fraction of Alport patients who undergo r enal transplantation develop anti-glomerular basement membrane (GBM) n ephritis, which results in loss of the renal allograft function. Recen tly, the target for alloantibodies from an X-linked Alport patient wit h complete COL4A5 gene deletion was determined to be the alpha 3 chain of type IV collagen. The present study characterized the post-transpl ant alloantibodies from an autosomal recessive Alport patient with ant i-GBM glomerulonephritis and a COL4A3 gene mutation which predicted a loss of 85% of the alpha 3(IV) NC1 domain. The specificity of these ne w antibodies were studied using glomerular basement membrane constitue nts and recombinant type IV collagen domains. The results establish th e target for the alloantibodies. from an autosomal recessive Alport pa tient with COL4A3 deletion as principally the alpha 3(IV) collagen cha in, similar to the post-transplant alloantibodies from X-linked Alport patients with COL4A5 gene deletions. The absence of alpha 3(IV) chain in the GBM of patients with both these forms of Alport syndrome, due either to a failure of synthesis or a failure of assembly, presumably leads to a loss of immunologic tolerance for the alpha 3(IV) NC1 domai n in transplanted allografts.