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

Normal glomerular capillaries filter plasma through a basement membrane (GBM) rich in α3(IV), α4(IV), and α5(IV) chains of type IV collagen. We now show that these latter isoforms are absent binchemically from the glomeruli in patients with X-linked Alport syndrome (XAS). Their GBM instead retain a fetal distribution of α1(IV) and α2(IV) isoforms because they fail to developmentally switch their α-chain use. The anomalous persistence of these fetal isoforms of type IV collagen in the GBM in XAS also confers an unexpected increase in susceptibility to proteolytic attack by collagenases and cathepsins. The incorporation of cysteine-rich α3(IV), α4(IV), and α5(IV) chains into specialized basement membranes like the GBM 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 GBM from XAS may explain the progressive basement membrane splitting and increased damage as these kidneys deteriorate.