COL4A5 GENE DELETION AND PRODUCTION OF POSTTRANSPLANT ANTI-ALPHA-3(IV) COLLAGEN ALLOANTIBODIES IN ALPORT SYNDROME

Mutations in the COL4A5 gene encoding the alpha 5(IV) chain of type IV collagen have been implicated as the primary defect in X-linked Alpor t syndrome. Several kinds of mutations have been reported so far, span ning point mutations to complete gene deletions. About 5% of Alport pa tients, who undergo renal transplantation, develop anti-glomerular bas ement membrane (GBM) nephritis, causing loss of allograft function. In one such patient, COL4A5 gene deletion was recently identified. In th e present study, the GBM constituent, targeted by the anti-GBM alloant ibodies from the patient who had complete COL4A5 gene deletion was ide ntified. Its identity was determined on the basis of circulating antib ody binding to various GBM constituents, domains of bovine type IV col lagen and recombinant NC1 domain of human type IV collagen. These resu lts establish, for the first time, the absence of the alpha 5(IV) chai n in Alport GBM and, in the same patient, the production of an alloant ibody that is targeted to a different chain of type IV collagen, the a lpha 3(IV) chain. These findings provide further support for the hypot hesis that: (1) anti-alpha 3(IV) collagen alloantibodies mediate the a llograft glomerulonephritis; and (2) COL4A5 gene mutations cause defec tive assembly of the alpha 3(IV) chain in Alport GBM, as reflected by the production of anti-alpha 3(IV) alloantibodies.