COL4A4

Many variants (also called mutations) in the COL4A4 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 alpha4(IV) collagen chain combines with other collagen IV chains. Other variants in the COL4A4 gene severely decrease or prevent the production of alpha4(IV) chains. 

These changes in the structure or amount of alpha4(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 in this gene can also lead to 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 COL4A4 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 COL4A4 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 COL4A4 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.