Isoform switching of type IV collagen is developmentally arrested in X-linked alport syndrome leading to increased susceptibility of renal basement membranes to endoproteolysis

Normal glomerular capillaries filter plasma through a basement membrane (GBM) rich in alpha 3(IV), alpha 4(IV), and alpha 5(IV) chains of type IV collagen, We now show that these latter isoforms are absent biochemically from the glomeruli in patients with X-linked Alport syndrome (XAS). Their GEM instead retain a fetal distribution of alpha 1(IV) and alpha 2(IV) isoforms because they fail to developmentally switch their a-chain use. The anomalous persistence of these fetal isoforms of type IV collagen in the GEM in XAS also confers an unexpected increase in susceptibility to proteolytic attack by collagenases and cathepsins. The incorporation of cysteine-rich alpha 3(IV), alpha 4(IV), and alpha 5(IV) chains into specialized basement membranes like the GEM may have normally evolved to protectively enhance their resistance to proteolytic degradation at the site of glomerular filtration, The relative absence of these potentially protective collagen IV isoforms in GEM from XAS may explain the progressive basement membrane splitting and increased damage as these kidneys deteriorate.