HOORAY! HOORAY! THE PXE GENE IS FOUND!!!

Listen

Click to listen (3.91 MB)

By: Kenneth H. Neldner, M.D.
By:  Berthold Struk, M.D.

Prologue

NAPE is pleased to announce the very exciting news that the PXE gene has been found! The name of the gene is ABC-C6.

Many of you have already become aware of the discovery, and all NAPE members are invited to “celebrate the event” at our annual meeting taking place in St. Louis, Missouri on the St. Louis University campus the weekend of July 21, 2000. Drs. Klaus Lindpaintner and Berthold Struk from Harvard lab are expected to be with us to share their experience in the discovery of the PXE gene.

One of the purposes for this special edition of the newsletter is to announce our findings in much the same way as we announced our discovery of the PXE locus. You may recall receiving a special edition of PXE Awareness in 1997 when our research group discovered that chromosome 16 was the one carrying the PXE gene. Now we have identified the gene itself.

Another reason for this special edition is that I know many of you have been asking what has been going on with the gene search and why you have received multiple mailings which have left many of you confused and a little bewildered. I’ll attempt to summarize the major aspects and bring you up to date.

A confusing factor is that everyone working on the gene-mapping project understandably wants to establish priority and “bragging rights” as to being the one that first identified the gene. If any of you have been working intensely on the project, you would better understand the personal feelings involved. Or, to bring it right down to earth, if you were riding a horse in a race, you would obviously like to see your horse come in first, even if only “by a nose.”

History

The history of the gene-mapping project is involved and even a bit controversial. I’ll try to summarize the salient points from a historical perspective.

After studying, researching, and writing about PXE for almost 25 years, it became obvious to me that we needed to know the gene responsible for the disorder if additional advances were to be made. Furthermore, in the late 1980’s and early 90’s tremendous technological advances created new opportunities for genetic research.

During a chance meeting in 1993 with Dr. Klaus Lindpaintner from Harvard University, who was at my home institution of Texas Tech University Health Sciences Center to give a genetics seminar, I asked him if he would be interested in taking on a new disorder called PXE. Somewhat to my surprise, he said yes, provided that I could find at least 50 families with two or more affected and unaffected members of the kinships. I said I would give it my best shot and thus, in 1993, the gene-mapping project was launched.

With the combined resources of the NAPE membership list and my own PXE patients whom I had personally seen, examined, studied, and counseled over the years, I soon was able to come up with more than the required 50 families. Blood samples were obtained and sent to the Harvard lab. Since my meeting with Dr. Lindpaintner, Dr. Berthold Struk had joined Dr. Lindpaintner and was given direct responsibility for the PXE genetic project. The laboratory side of the project began in earnest by mid 1995.

In 1997, the Harvard University-Lindpaintner-Struk/Texas Tech University-Neldner group published its 1996 discovery of the genetic locus of PXE – that chromosome 16 is the chromosome on which the abnormal PXE gene resides. Since such a chromosome region can carry a considerable number (100 or more) of individual genes, it then became a challenge to find “the needle in the haystack,”

Once the chromosome region was identified, several other labs became actively interested in pursuing the search for the gene, each hoping to win the race. In addition to our NAPE/Harvard group, these groups include the Hawaii group (Dr. Charles Boyd), Holland group (Dr. Arthur Bergen), and Philadelphia group (Dr. Jouni Uitto).

The race track soon became a little bumpy. I had called a meeting in August 1997 of interested PXE researchers in an effort to combine forces and establish a consortium agreement to organize a plan for combining our efforts for further PXE research. This meant that the research groups would work together, sharing data, to speed what we knew would be a complex, labor-intensive, and expensive gene search.

The consortium soon ran into difficulties. Questions over possible inappropriate use of shared data resulted in the breakdown of the consortium, leaving four individual labs to work independently.

The Bottom Line

The race turned out to have a “photo finish” with “four noses” crossing the finish line at essentially the same time. For those of you who like to split hairs, it was as follows:

  • May 23, 2000: The Philadelphia group published findings of the gene in the Proceedings of the National Academy of Sciences.

  • May 26, 2000: The Harvard group published its account of the identification of the gene in the Journal of Molecular Medicine.

  • June 1, 2000: The Hawaii and the Holland groups published back-to-back identical discoveries of the gene in Nature Genetics.

The past few years, and even more so the past few weeks, represent a milestone in PXE research no matter who wins the academic race. For now and for the future, the true and only winners are and will be the patients for whom and with whose help this work has been carried out. YOU are the real winners!

By: Kenneth H. Neldner, M.D. Special Edition (June 2000)

THE PXE GENE

Introduction

        Gene hunting is often quite a competitive business, with groups of scientists trying to beat each other to the finish line. The end of May 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. Patients with PXE can feel a certain amount of comfort in the fact that multiple researchers are interested in and working on their disorder, and should feel reassured in this latest research effort that the research of all groups led to the same ABC-C6 gene.

The Gene – Some Basic Knowledge

ABC-C6 is one of the many members of a group – or so-called “super family” – of genes known as Adenosine triphosphate Binding Cassette 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 other mammals) simple organisms such as worms or even bakers’ 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 cystic fibrosis, which have no known clinical relationship to PXE.

All members of the ABC family of genes have in common that they transport certain molecules across cell membranes, either into or out of the cell. To do so, they are fueled by a form of energy called ATP. The transported molecules can be lipids, electrolytes (like sodium, calcium or potassium), drugs, and many others. It is not clear which molecules the ABC-C6 transports. Whatever these molecules are, they must play an important role in keeping elastic fibers healthy, because we now know, if they malfunction, the elastic fibers lose proper function, leading to PXE.

Finding out precisely why and how a loss of function of the 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; namely, 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 much certain that PXE is a “recessive” disorder.

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 disorders, the illness occurs only if both copies are malfunctioning. Thus, in PXE, an affected individual inherited two malfunctioning copies of the ABC-C6 gene.

We have known for some time that there is about a 1 in 50,000 to 1 in 100,000 chance that anyone on earth will have PXE. This means that 1 in 150 people carry one malfunctioning copy of the gene, without a hint or sign (or with minimal hints or signs) of PXE. These numbers can be further projected to say that the chance of a couple with no personal or family history of PXE who then have a child with PXE is very slim (1 in 25,000). This is obviously too rare to warrant screening the entire population for the possibility of carrying a PXE gene that is totally unknown to them.

If a person with PXE should mate with someone who has two normal genes (not a carrier), all of their children will be carriers of the PXE gene; but, since none of the children will have two copies of the defective gene, none will have PXE.

On the other hand, if there is one parent with PXE and the other without PXE who, unknown to them, is a carrier of the PXE gene, the chances of their having a child with PXE are 50/50. Genetic testing before they become parents would be of value in such cases.

If couples are related, such as first or second cousins, the possibility of bringing two carriers together is much greater.

THANK YOU, NAPE!

Even though there has been much publicity about the role of PXE International in finding the gene, it is important for NAPE members to know that it was through them, before PXE International entered the scene, that the Neldner-Lindpaintner-Struk team made the critical discoveries that led to the gene. Science magazine acknowledges this fact appropriately in its June 2, 2000 issue in which Elizabeth Pennisi’s article gives a review of the PXE gene search.

We would like to extend a heartfelt THANK YOU to the patients and family members who participated in the genetics studies that led to the identification of the gene, and an equally big THANK YOU to those of you who gave financial support to the research that led to the gene. It is through your personal and financial contributions that the future now looks much brighter for anyone affected by PXE. At the same time, we appeal to you to continue to make progress in solving all the puzzles of PXE.

By:  Berthold Struk, M.D. Special Edition (June 2000)