Alport syndrome, a condition that primarily affects the kidneys, eyes, and inner ears, is caused by mutations in the COL4A5COL4A3, and COL4A4 genes. These three genes provide instructions for the production of different amino acid chains that, when combined, make up type IV collagen, a structural protein that plays a vital role in the kidneys, eyes, and inner ears.

Genetic mutations and Alport syndrome

Genetic mutations can cause the production of faulty or inefficient proteins or can completely prevent the production of vital proteins. It is thought that the variable rate of progression and symptom severity may be related to the specific type and location of genetic mutation on the COL4A3, or COL4A4, and COL4A5 genes. (More than 1,000 distinct mutations in the COL4A5 gene alone have been linked to Alport syndrome).

Some of these mutations may appear as a microdeletion, which is a missing portion of the gene and contributes to a loss of function in a group of genes that includes the COL4A5, COL4A3, or COL4A4 genes.

The COL4A5 gene is located on the X chromosome, while the COL4A3 and COL4A4 genes are both located on chromosome 2. Because COL4A5 is found on a sex chromosome, this form of Alport syndrome is inherited in an X-linked pattern, which is different than mutations found on non-sex chromosomes. X-linked Alport syndrome, which accounts for approximately 80 percent of cases, is more severe in males because they have only one X chromosome. Females have two X chromosomes, and the second X chromosome is usually able to compensate for a mutation in the first one.

Physiological mechanisms of Alport syndrome

Type IV collagen is the primary structural protein in the basement membrane, particularly those in the kidney, eye, and inner ear. The basement membrane is a thin membrane of proteins, fibers and other compounds separating the epithelium from the underlying tissue.

In the kidneys, the glomeruli, which are the primary filtering units for removing waste from the bloodstream, use basement membranes as filters. Urine passes through the membrane with all waste products, while blood remains in the body.

Without functional type IV collagen, the glomerular basement membrane develops holes. In an attempt to patch the holes, the body may develop scar tissue, which does not have the same properties as a basement membrane, and can render the glomeruli useless. This can ultimately lead to kidney failure.

Similarly, structures in the eye and ears that depend on type IV collagen for support may start to degrade. Although scar tissue generally does not form in the eyes and ears, the degeneration of these structures alone can lead to vision impairment and deafness.

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