Background. In X-linked Alport syndrome, mutations in the COL4A5 gene
encoding the alpha 5 chain of type IV collagen result in progressive r
enal failure. This nephropathy appears to relate to the arrest of a sw
itch from an alpha 1/alpha 2 to an alpha 3/alpha 4/alpha 5 network of
type IV collagen in the developing glomerular basement membrane (GBM;
Kalluri ct al, J Clin Invest 99:2470, 1997). Methods. We examined the
role of this switch in glomerular development and function using a can
ine model of X-linked nephritis with a COL4A5 mutation. The electron m
icroscopic appearance and the expression of the alpha 1-alpha 6 chains
of type IV collagen in the GEM was correlated with glomerular functio
n. Results. In normal neonatal glomeruli, once capillary loops were pr
esent, there was staining of GEM for the alpha 1-alpha 5 chains. Prior
to this stage, only alpha 1 and alpha 2 chains were present, with rar
e glomeruli positive for the alpha 5 chain. As glomeruli matured, the
alpha 1 and alpha 2 chains tended to disappear from the GEM, with the
alpha 3-alpha 5 chains remaining. In affected male dogs, only the alph
a 1 and alpha 2 chains were detected at any stage. GEM ultrastructure
in these dogs remained normal until one month and proteinuria did not
appear until two months. Conclusion. Our results show that normal glom
erular development involves a switch in type IV collagen networks. In
affected male dogs, a failure of this switch results in an absence of
the alpha 3/alpha 4/alpha 5 network and a persistence of the alpha 1/a
lpha 2 network in GEM. GEM ultrastructure and glomerular function rema
in normal for one month, indicating that GEM deterioration in Alport s
yndrome begins as a postnatal process. Hence, only the alpha 1/alpha 2
network is essential for normal glomerular development, whereas the a
lpha 3/alpha 4/alpha 5 network is essential for long-term maintenance
of glomerular structure and function.