| MESSAGE
FROM THE PRESIDENT
I am delighted to write to
you at the start of this New Year to summarize
our achievements of 2002 and look ahead at all
we will accomplish in 2003.
2002 was a major growth year for
Conquer Fragile X Foundation. We added three new
exciting projects, each with first rate investigators
at top-notch laboratories. Gary Bassell and his
team at the Albert Einstein College of Medicine
are working to align and coordinate the fragile
X research at his own lab and that of Bob and
Jennifer Darnell at Rockefeller and Mark Bear
at Brown University. Dr. Bassell’s team
is in the running to become one of the new NIH-funded
Fragile X Research Centers of Excellence in early
2003 and we wish them the best of luck. Dr. Yolanda
de Diego is working in Malaga, Spain to try some
antioxidant compounds as a treatment to reequilibrate
the oxidative system on the FMR1 knockout mouse
and to study the behavioral profile of these animals
and their response to the treatments. She reports
that the early results are very positive. And,
Dr. Assam el-Osta, a recent addition to the CFXF
Board of Scientific Advisors, is now the Senior
Research Investigator at the new Baker Institute
in Melbourne, Australia. Dr. el-Osta has brought
all his enthusiasm and energy for fragile X research
to his new position and we have gained a new and
aggressive fragile X research site in Australia!
Throughout 2003 we will work closely with all
our investigators as we watch their projects develop.
We have added two new Scientific
Advisors to our team. Dr. Karen Usdin, a Senior
Investigator at the NIH has joined us, as has
Dr. Pietro Chiurazzi of the Catholic University
in Rome, Italy. We welcome them and look forward
to putting their skills and experience to work
for us. They join the ranks of our excellent Scientific
Advisory Board that will guide our funding and
research decisions in 2003.
The International Fragile X Conference
in Chicago in July re-energized the entire fragile
X research and family community. The National
Fragile X Foundation and their Chicago affiliate
did an exceptional job organizing what, by any
standard, is a very large conference. They worked
diligently to provide a forum for families, researchers
and practitioners to share ideas, experiences
and information. CFXF enjoyed great visibility
at that conference; hundreds of people learned
about us and what we do. In 2003 we will work
to keep the positive momentum going and to become
even more widely known in the research community.
We have been very busy throughout
the past year working with the Coalition for Children’s
Health, with the NIH and the new CDC Center for
Birth Defects, Developmental Disabilities and
Disability and Health. Each of these organizations
provides a piece to the puzzle of public research
funding and each plays an important role in keeping
fragile X a medical research priority. Karen Fay,
our Grant and Funding Manager will chair the Membership
and Development Committee for the Coalition in
2003 and will continue to represent CFXF on the
new CDC Center’s Partners Committee Workgroups.
The National Fragile X Foundation and FRAXA are
also represented within these important groups
and together we have been very successful in seeing
that fragile X remains a medical research priority.
As always, none of this would be
possible without the generosity and support of
our donors, to whom we are very grateful. Our
Scientific Advisors, researchers, and friends
are always mindful that your contributions to
our research efforts make our continued work toward
a cure a priority for all of us. I wish each of
you a happy, healthy and peaceful New Year, and
thank you once again for your continued support.
Harris Hollin
President
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MARYLAND
GROUP TOURS
DR. USDIN'S LAB
Karen Usdin, our newest Scientific Advisor, hosted
the Maryland Fragile X Resource Group at her NIH
facility in Bethesda, Maryland on September 9,
2002. Dr. Usdin presented a mini-seminar on fragile
X syndrome, which included the latest information
on the disorder, the focus of current scientific
research, and handouts for participants. She and
four lab assistants gave the group a tour of her
research facility and briefed them on the latest
technologies to test, analyze and determine the
existence of fragile X and its various parameters.
Dr. Usdin and her staff gave an outstanding presentation,
answering dozens of questions and providing very
personal attention to a curious group. In appreciation,
MDFXRG President, Kristen Head, presented Karen
with a lovely 2003 Thomas Kincade calendar. Since
most of us do not have access to Dr. Usdin's Maryland
labs, she has generously provided us the following
explanation of her current fragile X research.
Studying the
Causes and Consequences of the Unusual Mutation
Responsible for Fragile X Syndrome
Karen Usdin
Laboratory of Molecular & Cellular Biology
National Institute of Diabetes, Digestive and
Kidney Diseases National Institutes of Health
My research group at the NIH is studying the
unusual mutation responsible for fragile X syndrome.
We are also interested in the chain of events
set in motion by this mutation that led to the
loss of fragile X protein (FMRP), and thus to
the symptoms of this disorder. We thereby hope
to identify points in this process where intervention
to ameliorate fragile X symptoms may someday be
possible.
We are trying to understand these events at
the molecular level. Our early work focused on
the behavior of the fragile X repeats in vitro.
We and others showed that one strand of the repeat
forms a hairpin structure in which the DNA, as
the name suggests, folds back on itself to form
a structure that looks rather like a bobby pin.
The DNA also forms a second structure that resembles
a hairpin that has been folded in half. We showed
that this folded hairpin has a potentially significant
property: it blocks DNA synthesis very effectively.
It is thought such blocks may lead to the fragile
X mutation in a number of different ways. We are
currently trying to develop a good mouse model
to study this process, but have been hampered
by the apparent ability of mice to prevent or
correct such mutations. However, we are optimistic
that one set of mice we have recently generated,
which has a large number of repeats in its fmr1
gene, may be useful both for studying factors
that affect the mutational process as well as
the premature ovarian failure sometimes seen in
female carriers of “premutation” alleles,
and the tremor and ataxia seen in some male carriers.
We have also generated genetically modified human
cell lines that can be used to analyze the changes
in gene expression occurring in these carriers.
Our preliminary experiments have identified at
least one pathway that may be important in causing
the symptoms in these individuals.
We have also been studying how the full mutation
affects the regulation of the FMR1 gene. We have
identified 2 proteins that are critical for FMR1
gene function in unaffected individuals and “premutation”
carriers. We showed that the ability of one of
these proteins to activate the gene is blocked
by DNA methylation, the very modification of the
FMR1 gene that occurs in most fully affected individuals
and is responsible for the loss of FMRP. This
finding has repercussions for any attempts to
reactivate the gene. We are now expanding these
studies to try and develop a more complete picture
of the consequences of the fragile X mutation
that we hope may one day allow us to reduce or
even reverse its effects.
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