Why do some Alport syndrome females appear to have no symptoms while others have severe symptoms similar to males?
X-Inactivation in X-Linked Alport syndrome
If you have studied Alport syndrome at all you know that in general, the disease impacts males with X-linked Alport syndrome (XLAS) more severely and earlier in life than it affects females with XLAS. You may also have learned that women with XLAS can vary a great deal on how and if their disease progresses. This is at least partially due to a phenomenon known as X-inactivation.
When a child is conceived, they receive an X chromosome from the mother and an X or Y chromosome from the father. If the child receives their father’s X chromosome, that child is a girl. If it receives their father’s Y chromosome, that child is a boy. All girls/women have TWO X chromosomes and all boys/men have ONE X chromosome. The gene that is abnormal in Alport syndrome is found on the X chromosome. This fact causes X-linked Alport syndrome to progress differently in men and women.
Since females have two X’s but only need one, one X is always turned off in each cell by random chance (like the flip of a coin). The more often the X with the Alport mutation is turned on, the more likely a woman will have more severe disease. Only the “normal” X chromosome is able to make type IV collagen to put in the basement membrane. Under a microscope, most males with Alport syndrome will have absent type IV collagen in their kidney basement membranes, whereas females will have areas that are normal right next to areas that are abnormal, in a “mosaic” pattern. One analogy for how this looks in nature is to think of the fur on a calico cat. The gene affecting fur color is on the X chromosome and the cat’s fur color depends on which X is turned on in each patch of fur. A female’s basement membrane type IV collagen similarly presents in patches due to X-inactivation. A male’s membrane would be a consistent pattern, like a Tabby cat’s fur.
Autosomal Recessive and Autosomal Dominant Alport syndrome
For females with Autosomal Recessive Alport syndrome (ARAS), their disease is not affected by X-inactivation because the mutation is not passed on the X chromosome. Females with ARAS will progress to ESRD at the same rate as their male counterparts with that same mutation. Women and men with Autosomal Dominant Alport syndrome (ADAS) may or may not progress to renal failure, but again the mutation is not found on the X chromosome and X-inactivation is not relevant to this form of Alport syndrome.
Alport syndrome Genetics