COL4A3

Many variants (also called mutations) in the COL4A3 gene can cause Alport syndrome, a condition characterized by kidney disease, hearing loss, and eye abnormalities. Most of these variants change single protein building blocks (amino acids) in a region where the alpha3(IV) collagen chain combines with other collagen IV chains. Other variants in the COL4A3 gene severely decrease or prevent the production of alpha3(IV) chains. 

These changes in the structure or amount of alpha3(IV) chains severely impair the formation of alpha345(IV) collagen networks in the basement membranes of the kidney, inner ear, and eye. In the kidney, other types of collagen build up in the basement membranes, eventually scarring the kidneys and leading to kidney failure. Variants this gene can also lead to abnormal function in the inner ear, resulting in hearing loss, and changes in the lens of the eye and the light-sensitive tissue at the back of the eye (retina).

Variants in a single copy of the COL4A3 gene can cause a form of the condition called autosomal dominant Alport syndrome. Individuals with this form typically have the kidney problems that are characteristic of Alport syndrome, including blood in the urine (hematuria), excess amounts of protein in the urine (proteinuria), and a gradual loss of kidney function. 

Variants in both copies of the COL4A3 gene cause autosomal recessive Alport syndrome. Individuals with this form of the condition can have hearing loss and eye abnormalities in addition to kidney problems.

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A variant in one of the two copies of the COL4A3 gene can cause thin basement membrane nephropathy. People with this condition typically have blood in their urine (hematuria) but no other signs or symptoms of kidney disease. In the past, this condition was often called benign familial hematuria. Thin basement membrane nephropathy rarely progresses to kidney failure.

Goodpasture syndrome is a severe disease of the lungs and the kidneys caused by antibodies to the alpha3(IV) collagen chains. Antibodies are immune system proteins that normally attack foreign substances such as bacteria or viruses, but in people with Goodpasture syndrome, they target alpha3(IV) collagen chains. It remains unclear why some people's immune systems make antibodies to their own collagen chains. The antibodies cause inflammation when they attach (bind) to the basement membranes of blood vessels in the air sacs (alveoli) of the lungs and filtering units (glomeruli) of the kidneys. As a result, people with Goodpasture syndrome can develop kidney failure and bleeding in the lungs, which causes them to cough up blood. In some people, antibodies attack only the kidneys. These people are said to have anti-glomerular basement membrane nephritis.