A MONOCLONAL-ANTIBODY MARKER FOR ALPORT SYNDROME IDENTIFIES THE ALPORT ANTIGEN AS THE ALPHA-5 CHAIN OF TYPE-IV COLLAGEN

The nephropathy of Alport syndrome is associated with unique abnormali ties of glomerular basement membranes and is caused in many families b y mutations in the X-chromosomal gene COL4A5, which encodes the alpha 5 chain of type IV collagen. We have previously reported that Alport e pidermal and glomerular basement membranes fail to bind a monoclonal a ntibody, Mab A7, that reacts with normal epidermal and glomerular base ment membranes, and that this abnormality is unique to Alport syndrome . The molecule in normal tissues that reacts with Mab A7 was termed th e ''Alport antigen.'' In the present study we used recombinant carboxy terminal noncollagenous (NC1) domains of the alpha 1, alpha 2, alpha 3 , alpha 4 and alpha 5 chains of type IV collagen to determine the mole cular identity of the Alport antigen. Mab A7 was found to bind specifi cally to the NC1 domain of the alpha 5 chain of type IV collagen, by E LISA and immunoblotting studies. This finding provides a molecular exp lanation for the utility of Mab A7 as a marker for the Alport basement membrane defect. Mab A7 can identify the Alport basement membrane def ect in those patients in whom COL4A5 mutations prevent incorporation o f alpha 5(IV) into basement membranes.