Mutant-type α5(IV) collagen in a mild form of Alport syndrome has residual ability to form a heterotrimer

Abstract

Alport syndrome (AS) is caused by mutations in type IV collagen α3, α4, and α5 chains. The three chains form a heterotrimer. We have previously shown that all 15 types of recombinant α5(IV) chains with mutations, corresponding to AS mutations, in the noncollagenous (NC1) domain are defective in terms of heterotrimer formation and/or secretion of the heterotrimer from cells. A relatively large family with Cys1638Tyr in the NC1 domain of the α5(IV) chain has been found to have mild AS phenotypes without hearing loss or ocular abnormalities. Renal biopsies of different family members also revealed the presence of the α3(IV), α4(IV), and α5(IV) chains in the glomerular basement membrane. In our study, we introduced the mutation corresponding to Cys1638Tyr into the α5(IV) chain and characterized the mutant chain. In cells containing the mutant-type α5(IV) chain, heterotrimer formation in the cells and secretion of the α5(IV) chain in the monomeric form from the cells were markedly decreased compared with cells containing the wild-type chain. However, the heterotrimer that was formed from the mutant chain was still able to be secreted from the cells. The residual ability of the mutant chain may have led to the unique phenotypes found in the AS family with the Cys1638Tyr mutation.