Identification of ABC-C6 as the Gene that causes PXE

By Berthold Struk M.D.


Gene hunting is often quite a competitive business, with groups of scientists trying to beat each other to the finishing line. The end of May 2000 saw just such a dash, with four groups of researchers almost simultaneously publishing the discovery of the gene that lies at the root of PXE, a gene called ABC-C6.

However, regardless of which scientists got their report out first, the real winners are of course the patients for whom and with whose help this work has been carried out.

This is indeed exciting news, as it marks the second critical milestone, after the localization of the gene in 1997, on the way to a true understanding of the cause of the disease, and, hopefully, to its eventual treatment or prevention.

Latest developments

Franziska Ringpfeil from Jouni Uitto's group at Jefferson University published mutations within the coding region of the ABC-C6 gene as the cause of PXE in the Proceedings of the National Academy of Science (PNAS) May 23, 2000.

The Harvard Group, (Struk et al.) published a paper on mutations of the same gene as the cause of PXE in Families from Switzerland, Mexico and the USA in the 
Journal of Molecular Medicine on May 26, 2000.

There were two more papers that came out on June 2nd in Nature Genetics from research groups in Hawaii and the Netherlands, describing exactly the same gene as the cause of PXE.

The Gene - some basic knowledge

ABC-C6 is one of many members of a group (or so-called "superfamily") of genes called Adenosine triphosphate BindingCassette genes.

In the history of the development of genes, the ABC genes have been present for a very long time, indicating their importance for all things living. Thus, we find them even in such lowly and (compared to humans and mammals) simple organisms as worms or even baker's yeast.

We know from another perspective that these genes are important, because we already have examples that show us that malfunction of ABC genes causes many different diseases, such as, most widely known, cystic fibrosis.

All members of the ABC family of genes have in common that they transport certain molecules across the cell membrane, either into or out of the cell, and to do so, are fueled by a form of chemical energy called ATP. The transported molecules can be lipids, electrolytes (like sodium, calcium or potassium), drugs and many others. It is not clear what molecules the ABC-C6 transports.

Whatever these molecules are, they must play an important role in keeping the elastic fibres healthy, because - as we now know- if they malfunction, the elastic fibres lose their proper function, leading to PXE.

Finding out precisely why and how a loss of function of ABC-C6 leads to PXE will certainly be the next question researchers will tackle. The answer to this will hold important clues towards treating and/or preventing the illness.

What do the findings mean for PXE patients and their family members today?

There are generally two consequences of finding a disease-associated gene, diagnosis and treatment. We have just said that treatment will take a while, pending a complete understanding of the way ABC-C6 works.

What about diagnosis?

An important outcome of the current research is that we are now very certain that PXE is a "recessive" disease.

What does this mean?

We all carry two copies of every gene in our cells, one inherited from the father, the other from the mother. In recessive diseases, the illness only occurs if both copies are malfunctioning. Thus, in PXE, a patient needs to have inherited two malfunctioning copies of the ABC-C6 gene.

We have known for a long time that there is about a 1-in-50,000 to 100,000 chance that a person comes down with PXE. This means, that about 1 in 150 people carries one malfunctioning copy of the gene - completely without any hint of PXE, of course. The chance that 2 people who each carry one copy meet and have a family is very slim, 1 in 25,000, and this is way too rare to warrant screening everyone for the possibility that they carry one malfunctioning copy of the PXE gene. A person who him/herself has PXE, however, has a 1 in 150 chance of founding a family with a partner who carries one malfunctioning ABC-C6 copy, and they may want to know about this, because if they have children, they have a 50/50 chance of having PXE. Although the tests will not be straightforward, because we have already found a number of different mutations (changes) in the ABC-C6 gene, all of which can cause it to malfunction, such a couple now can -if they so chose- find out whether they have a 50/50 or a zero chance of having children with PXE. And once a pregnancy occurs, of course there now is the option of prenatal diagnosis

Thank You, PiXiE & NAPE

Even though there has been much publicity about the role of PXE-International in finding the gene, it is important for PiXiE & NAPE members to know that it was through them, long before PXE-International stepped up their activities, that the Neldner-Lindpaintner team made the critical discoveries that lead to the gene. An editorial in the magazine "Science" acknowledges this fact appropriately.

We would like to extend a heartfelt THANK YOU to all patients and family members for participating in these genetics studies that led to the identification of the gene.

At the same time, we appeal to you to continue to help us in the work that lies ahead, so that, together, we'll continue to make progress towards solving all the puzzles.

Berthold Struk, M.D.