GBM Collagens & Alport's Syndrome

Alport's Syndrome is a genetic disorder characterized by glomerulonephritis, progression to ESRD, and hearing loss. Intriguingly, it can be inherited in either an X-linked, autosomal recessive, or autosomal dominant manner. Why is the inheritance pattern so complex and what does it tell us about the biology of this interesting disease?

To answer this question we need to understand the composition of the glomerular basement membrane: in addition to being comprised of laminin, nidogen, and sulfated proteoglycans, a major component is collagen IV. There are 6 genes in humans which encode different alpha chains:

COL4A1 encodes alpha-1 collagen (Type IV).

COL4A2 encodes alpha-2 collagen (Type IV).

COL4A3 encodes alpha-3 collagen (Type IV).

COL4A4 encodes alpha-4 collagen (Type IV).

COL4A5 encodes alpha-5 collagen (Type V).

COL4A6 encodes alpha-6 collagen (Type VI).

Three different alpha-chains combine to form a triple helix called a "protomer" which is the fundamental structural unit of the collagen network. The particular collagen protomer which is the major player in the adult kidney is the alpha-3-alpha-4-alpha-5 promoter. Not surprisingly, then, mutations in any one of the three genes can cause Alport Syndrome.

The most common inheritance pattern is X-linked, which accounts for 85% of all cases of Alport Syndrome, and occurs due to mutations in the COL4A5 gene on the X-chromosome.

It is also possible to have autosomal recessive inheritance due to inherited mutations from both patients of either the COL4A3 or COL4A4 genes, both on somatic chromosomes.

Finally, there are rare cases of autosomal dominant inheritance of Alport Syndrome when dominant-negative mutations in either the COL4A3 or COL4A4 genes are inherited.