|
Researchers
Around the World Publish and Celebrate the Identification of
ABC-C6 as the Gene that Causes PXE.
Lead Article Posted
5/27/00
By Berthold Struk M.D.;
Introduction
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 sees 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 get 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)
on 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 will be two more papers coming 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 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 mammals) simple
organisms as worms or even bakerÕs 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
fibers healthy, because -as we now know- if they
malfunction, the elastic fibers 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, 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, 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.
The author:
Berthold Struk, M.D.
Brigham and Women's Hospital
221 Longwood Avenue, LMRC 209
Boston, MA 02115-5822
e-mail:
bs@calvin.bwh.harvard.edu
|
