Inheritance of Alport SyndromeType IV collagen is a family of six proteins, or chains, known as alpha-1 through alpha-6 chains. Alport syndrome is caused by mutations that affect the alpha-3, alpha-4 or alpha-5 type IV collagen chains.
Three genetic types of Alport syndrome exist. X-linked Alport syndrome is the most common form, accounting for. about 80% of people with the disease. X-linked Alport syndrome results from mutations in the gene that produces the alpha-5 chain of type IV collagen, which is located on the X chromosome. Males have only one X chromosome, so boys with mutations in the alpha-5 chain are severely affected and always develop kidney failure sometime in their lives, because they do not have a normal copy of the gene to buffer the effect of the mutant gene. Girls, who have two X chromosomes, have two copies of the alpha-5 chain gene. In girls with X-linked Alport syndrome, one copy of the alpha-5 chain gene carries a mutation, but the other copy is normal. The normal copy of the gene counters the effect of the mutation, so that girls with X-linked Alport syndrome usually have milder symptoms than boys. However, girls with X-linked Alport syndrome can also develop kidney failure.
Because men pass their X chromosomes to their daughters but not to their sons, a man with X-linked Alport syndrome will pass the disease to all of his daughters but his sons cannot inherit the disease. As for a woman with X-linked Alport syndrome, every time she is pregnant there is a 50:50 chance she will pass the X chromosome carrying the mutant alpha-5 chain gene (and the disease) to the baby, whether the baby is a girl or a boy.
About 15% of people with Alport syndrome have the autosomal recessive form of the disease. The genes that make the alpha-3 and alpha-4 type IV collagen chains are located on chromosome 2. Everyone has two copies of chromosome 2, so everyone has two copies of the alpha-3 and alpha-4 chain genes. Autosomal recessive Alport syndrome results when a person has mutations in both copies of the alpha-3 chain gene or the alpha-4 chain gene. Unlike X-linked Alport syndrome, the autosomal recessive type affects girls just as severely as boys.
A person with autosomal recessive Alport syndrome can only pass one of his or her mutant copies of the alpha-3 or alpha-4 chain gene to a child, so the risk of passing this type of disease to children is almost zero. However, each child of a person with autosomal recessive Alport syndrome will carry one mutant copy of the affected gene. People with one mutant copy of the alpha-3 or alpha-4 chain gene may have blood in their urine (see below), but development of kidney failure is very unusual.
About 5% of people with Alport syndrome have the autosomal dominant form of the disease. These people have one mutant copy of the alpha-3 or alpha-4 chain gene. Most of these people will have blood in their urine, without any other symptoms of kidney disease such as protein in the urine or high blood pressure. People carrying a mutation in one copy of the alpha-3 or alpha-4 chain gene who have blood in the urine without any other symptoms of kidney disease, and no family history of kidney failure, are said to have Thin Basement Membrane Nephropathy. On occasion, a person with a mutation in one copy of the alpha-3 or alpha-4 chain gene has protein in the urine and other symptoms of kidney disease in addition to blood in the urine. These people are said to have autosomal dominant Alport syndrome.
Every time a person with a mutation in one copy of the alpha-3 or alpha-4 chain gene has a child, there is a 50:50 chance that the child will inherit the mutant copy of the gene. This explains why most people with Thin Basement Membrane Nephropathy have relatives who have blood in their urine.