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 membran e (GBM) rich in alpha 3(IV), alpha 4(IV), and alpha 5(IV) chains of ty pe IV collagen, We now show that these latter isoforms are absent bioc hemically from the glomeruli in patients with X-linked Alport syndrome (XAS). Their GEM instead retain a fetal distribution of alpha 1(IV) a nd alpha 2(IV) isoforms because they fail to developmentally switch th eir 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 cathepsin s. The incorporation of cysteine-rich alpha 3(IV), alpha 4(IV), and al pha 5(IV) chains into specialized basement membranes like the GEM may have normally evolved to protectively enhance their resistance to prot eolytic degradation at the site of glomerular filtration, The relative absence of these potentially protective collagen IV isoforms in GEM f rom XAS may explain the progressive basement membrane splitting and in creased damage as these kidneys deteriorate.