Alport Syndrome - Causes

Causes

Alport syndrome is caused by mutations in COL4A3, COL4A4, and COL4A5, collagen biosynthesis genes. Mutations in any of these genes prevent the proper production or assembly of the type IV collagen network, which is an important structural component of basement membranes in the kidney, inner ear, and eye. Basement membranes are thin, sheet-like structures that separate and support cells in many tissues. When mutations prevent the formation of type IV collagen fibers, the basement membranes of the kidneys are not able to filter waste products from the blood and create urine normally, allowing blood and protein into the urine.

The abnormalities of type IV collagen in kidney basement membranes cause gradual scarring of the kidneys, eventually leading to kidney failure in many people with the disease. Progression of the disease leads to basement membrane thickening and gives a "basket-weave" appearance from splitting of the lamina densa. Single molecule computational studies of type IV collagen molecules have shown changes in the structure and nanomechanical behavior of mutated molecules, notably leading to a bent molecular shape with kinks.