What is Alport syndrome, and what causes it?

[Anonymous]

What is Alport syndrome, and what causes it?

[Genetic Counselor]

Alport syndrome is a genetic condition that damages the tiny filtering units inside the kidneys over time, and it often affects hearing and vision as well. It happens because of changes, called pathogenic variants, in one of three genes – COL4A3, COL4A4, or COL4A5 – that carry the instructions for building type IV collagen, a protein that forms part of the scaffolding found in thin sheets of tissue called basement membranes. These basement membranes sit underneath the filtering units of the kidney, inside the inner ear, and within the lens and retina of the eye, which is why a single gene change can affect all three organs at once even though they seem unrelated.

In a healthy kidney filter, the basement membrane relies on a specific network built from three collagen chains working together – the very chains that COL4A3, COL4A4, and COL4A5 provide instructions for. When one of these genes is altered, that network cannot form correctly. The basement membrane becomes abnormally thin in some areas and abnormally thick, split, or layered in others. Over years, this structural weakness lets red blood cells and, eventually, protein leak into the urine, and it triggers ongoing scarring that gradually reduces how well the kidneys filter blood.

Which gene is involved shapes both how Alport syndrome is passed down in a family and how severe it tends to be:
• COL4A5, located on the X chromosome, is changed in around 4 out of every 5 families with Alport syndrome. This form is called X-linked Alport syndrome.
• COL4A3 and COL4A4, located on chromosome 2, together account for most of the remaining families. When a person inherits an altered copy from both parents, it is called autosomal recessive Alport syndrome; when a single altered copy causes a milder, later-onset form on its own, it is called autosomal dominant Alport syndrome.
• Digenic Alport syndrome, in which a person carries pathogenic variants in two of the three genes at once, is rare and tends to cause disease of a severity in between the other forms.
Because the underlying problem is structural – a scaffolding protein that is not built correctly – rather than a toxin or infection, Alport syndrome cannot be caught from another person and nothing the family did caused it.

[Author]

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