The gene associated with PXE is called ABCC6. You, like all people, have two copies of the ABCC6 gene, one from your mother and one from your father. People affected by PXE have mutations (changes) in the ABCC6 gene. PXE is a recessive trait, which means that a mutation in just one copy of the gene will not cause PXE. A person must have mutations in both copies of the gene to have PXE. This is called autosomal recessive inheritance, and it means that it takes two mutated genes to cause a disease.

Figure 1 is a drawing of family tree used to show inheritance of genetic traits, called a pedigree. In this drawing, circles are female and squares are male. An uppercase “P” stands for an ABCC6 gene without any mutations in the gene. A lower case “p” stands for an ABCC6 gene with mutations that cause PXE. A colored-in circle (female) or square (male) means the person is affected with PXE. A circle or square that is half shaded represents a carrier.

Imagine that you are the circle labeled “You”. In this drawing, your mother and father each carry a single copy each of a changed copy of ABCC6, and an unchanged copy of ABCC6 – and half of their symbol is colored in. Notice that your parents are each carriers of the mutation for PXE, and neither one has PXE, because they have one ABCC6 gene without any mutations, and this gene functions well enough to override most of the effects of the other mutated gene. However they have both passed their mutated gene to you, so you are affected by PXE (your circle is completely colored in).

In addition, any of your siblings with two mutated ABCC6 genes are affected by PXE; those who have no mutations in at least one ABCC6 gene do not have PXE, and those with a mutation in one ABCC6 gene are carriers.

Figure 2

Let´s look at your chances of inheriting PXE from your two parents who are carriers using Figure 2 above, called a Punnett square. Your mother and father both have one ABCC6 gene with no mutation (labeled uppercase “P”); and they are both also carriers of a mutation (labeled lower case “p”). Therefore, each parent has a 50% chance of passing on a mutated ABCC6 gene, and a 50% chance of passing on an ABCC6 gene without a mutation to each child. Figure 2 shows all the potential combinations of genotypes that can occur in children of your parents. You can see that for each offspring, there is a 50% (one out of two) chance that a child receives only one gene with the PXE mutation and the offspring is a carrier (“Pp” - like Jack in Figure 1). There is a 25% (one out of four) chance that a child receives no gene with the PXE mutation and the offspring is not affected by PXE and is not a carrier (“PP” - like Jane in Figure 1). You can also see that there is a 25% (one out of four) chance with each pregnancy that an offspring will get two PXE mutations (“pp”), and be affected like you or Paul in Figure 1.

You may notice that the family in Figure 1 does not have the “right” percentages – the odds are that 50% of the offspring should be carriers and only 25% of offspring should be affected. But, odds do not dictate results. When you flip a coin it should come up heads or tails each 50% of the time, but you know you can “beat the odds” and have a string of heads or tails for a while. Statistically it works out, but isolated and small sequences might not fit the odds.

Now look at Figure 3. Here is another family that “beat the odds”.

Figure 3

If you do not see any individuals with PXE in your family in the generations before and after you, is that unusual? No. It is very common in PXE families and in any family with a recessive disease. Most individuals have either no other affected relatives or just siblings with PXE. This is because PXE is autosomal recessive and PXE will not show up in your family again unless a carrier or affected individual marries another carrier. We see this situation in Figure 4.

Figure 4
Affected individual (Paul) has children
with carrier (Mary)

This is the same pedigree as in Figure 1, but now Paul has had offspring with Mary, a carrier of PXE. This pedigree makes it look like his family is experiencing autosomal dominant inheritance where only one changed gene is required for symptoms to be present, but in fact he has had offspring with a carrier of the mutated gene and so he can have children affected by PXE.

When does PXE appear in more than one generation?

Two possible reasons are as follows:

A high carrier frequency. This means that there are many people in the general population with one changed copy of the ABCC6 gene. In some families, people who have PXE have had children with people who are carriers. In this situation, there is a 50% chance of having a child with PXE, but it is still autosomal recessive inheritance.

Parental consanguinity. This means that the parents of the child with PXE are related to each other. When people are related, they have a higher chance of having the same changed gene that has been passed down to them from their common ancestor. This situation puts them at higher risk to have a child who may inherit the same changed gene and have a recessive problem like PXE.