COL4A5 Gene - Alport's Syndrome

COL4A5 gene is “Collagen, type IV, alpha 5.”

Where is the COL4A5 gene located?

Cytogenetic Location: Xq22

The COL4A5 gene is located on the long (q) arm of the X chromosome at position 22.

Normal function of the COL4A5 gene.

The COL4A5 gene provides instructions for making one component of type IV collagen. Specifically, this gene makes the alpha5(IV) chain of type IV collagen. This chain combines with two other types of alpha (IV) chains (the alpha3 and alpha4 chains) to make a complete type IV collagen molecule. These networks make up a large portion of basement membranes, Type IV collagen alpha 3-4-5 networks play an especially important role in the basement membranes of the kidney, inner ear, and eye.

Diseases associated with COL4A5 mutations:

Alport syndrome - caused by mutations in the COL4A5 gene

More than 400 mutations in the COL4A5 gene have been found to cause Alport syndrome. Most of these mutations change single protein building blocks (amino acids) in a region where the alpha5 (IV) collagen chain combines with other type IV collagen chains. Other mutations in the COL4A5 gene severely decrease or prevent the production of alpha5 (IV) chains. As a result, there is a serious deficiency of the type IV collagen alpha 3-4-5 network in the basement membranes of the kidney, inner ear, and eye. In the kidney, other types of collagen accumulate in the basement membranes, eventually leading to scarring of the kidneys and kidney failure. Mutations in this gene can also lead to abnormal function in the inner ear, resulting in hearing loss.

Classically, patients with Alport's syndrome develop hematuria, thinning and splitting of the GBMs, mild proteinuria (<1–2 g/24 h), which appears late in the course, followed by chronic glomerulosclerosis leading to renal failure in association with sensorineural deafness. Some patients develop lenticonus of the anterior lens capsule, "dot and fleck" retinopathy, and rarely, mental retardation or leiomyomatosis. Approximately 85% of patients with Alport's syndrome have an X-linked inheritance of mutations in the 5(IV) collagen chain on chromosome Xq22–24. Female carriers have variable penetrance depending on the type of mutation or the degree of mosaicism created by X inactivation. Fifteen percent of patients have autosomal recessive disease of the 3(IV) or 4(IV) chains on chromosome 2q35–37. Rarely, some kindred have an autosomal dominant inheritance of dominant-negative mutations in 3(IV) or 4(IV) chains.