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When the Mental Retardation and Developmental Disabilities
Research Center (MRDDRC) at Baylor College of Medicine (BCM) was established
in August of 1988, neurology had not yet benefited from the newly emerging
tools of genetics. The field had yet to determine what mutations caused
even the most common forms of mental retardation and developmental delay
or how we might go about treating such disorders. The MRDDRC at BCM
created an infrastructure of core facilities to support investigators
interested in identifying the causes of mental retardation and dissecting
the pathogenesis of various human conditions that lead to disability.
These cores have been instrumental to the remarkable discoveries that
were to come.
The MRDDRC at BCM currently supports the research of over
40 investigators studying abnormalities in human development. The joint
benefits of improved diagnosis, better patient care, and deeper understanding
of human biology have come directly from MRDDRC support for research
leading to the discovery of the molecular basis of Stargardt syndrome,
Miller-Dieker syndrome, glycerol kinase deficiency, 1p36 deletion syndrome,
Smith-Magenis disease, Prader-Willi Syndrome and Angelman Syndrome,
among others. The MRDDRC at BCM has been a crucial player in all these
discoveries, and BCM’s technological advances — multicolor
FISH, genetic engineering in the mouse, shot-gun cloning and large-scale
sequencing —have in turn strengthened the ability of the cores
to support BCM’s research endeavors and laid the groundwork for
BCM’s Human Genome Sequencing Center. The cores for neuropathological
analysis, embryonic stem cell work, generating transgenic mice and performing
neurobehavioral and synaptic plasticity analyses (to name a few) concentrate
expertise and make it accessible to investigators who would otherwise
have to find ways to import these technologies and develop these skills
in their own labs. The MRDDRC is an impressive venue for facilitating
research in a cost-efficient way.
The combination of these research accomplishments and
an interactive group of MRDDRC investigators created a clear identity
for Mental Retardation and Developmental Disabilities (MRDD) research
at Baylor College of Medicine (BCM). BCM faculty have made numerous
contributions towards understanding the etiology and pathogenesis of
several leading causes of MRDD and are recognized as leading experts
for these disorders. The labs of David Nelson Ph.D., James Lupski M.D.,
Ph.D., and Huda Zoghbi M.D. are a few examples that have been highlighted
to demonstrate some of MRDDRC successes.
 Dr.
Nelson and his collaborators discovered the dynamic nature of the Fragile
X mutation, which provided an elegant explanation for the increasing
severity of the disease upon transmission to another generation. Further
studies on trinucleotide repeats at BCM not only allowed the identification
of numerous disease genes, such as those causing myotonic dystrophy,
Friedreich’s ataxia and several spinocerebellar ataxias, but lent
insight into the mechanisms contributing to triplet repeat instability
and disease pathogenesis.
Another important success story is Dr. Lupski’s
discovery that single gene dosage can be as important (and liable to
disruption) as sequence integrity. His studies of the dosage-sensitive
myelin gene PMP22 led to the discovery that duplications and deletions
are caused by aberrant recombination between repeated sequences. Such
a mechanism has now been shown to account for deletions in other disorders
such as Williams syndrome, Smith-Magenis syndrome, velocardiofacial
syndrome, and type 1 neurofibromatosis. The realization that these “genomic
disorders” are a rather common source of MR and DD has led to
new efforts to identify additional such repeats as candidates for similar
mutations.
The discovery in the Zoghbi Lab of the genetic basis of
Rett syndrome made clear the importance of epigenetic modifications
in brain function. Disruptions in MeCP2 turn out to be responsible not
only for Rett syndrome, one of the most common causes of mental retardation,
but also for a broad spectrum of phenotypes ranging from autism, non-syndromic
retardation or affective disorders to neonatal encephalopathy. The MRDDRC
cores have allowed BCM scientists to generate and characterize a remarkable
mouse model of this disease. Work on UBE3A in the Dr. Arthur Beaudet's
laboratory is probing the epigenetic pathways controlling neuronal function
and integrity in Angelman Syndrome and Autism.
Huda Zoghbi, M.D. was appointed director
in 1994 upon recommendation of the internal advisory committee after
Dr. Edward McCabe, BCM MRDDRC founding principal investigator and director,
left BCM to chair pediatrics at UCLA. Dr. Zoghbi has been director of
the BCM MRDDRC for over eight years and will continue in that capacity.
She is a board certified pediatric neurologist with abundant research
accomplishments. She brings interest in and experience with numerous
human genetic disorders with mental retardation as a component. She
has a particular interest in Rett syndrome. Dr. Zoghbi is professor
of pediatrics, neurology, neurosciences, and molecular and human genetics
as well as an investigator of the Howard Hughes Medical Institute (HHMI).
David Nelson, Ph.D. has served as associate
director of the BCM MRDDRC during the current funding cycle, and will
continue in that role in this proposed renewal. Dr. Nelson is a human
molecular geneticist who brings extensive experience and interest in
mental retardation to the MRDDRC through his activities in characterizing
the Fragile X syndrome, FRAXE syndrome and Incontinentia Pigmenti genes
and their products. He also has prior experience in managing large centers
as both associate director and director of the National Institutes of
Health (NIH) funded BCM Human Genome Sequencing Center (BCM-HGSC). Dr.
Nelson will be responsible for the BCM MRDDRC should the director become
incapacitated and he will continue to advise and assist the director
in the operation of the MRDDRC along with the Administrative and Scientific
Advisory Committee (ASAC).
The internal Administrative and Scientific Advisory Committee
(ASAC) assists the director and associate director with long-term planning,
operations and policy issues within the MRDDRC. The members of this
committee are:
William R. Brinkley, Ph.D. is vice president
for graduate sciences and dean of the Graduate School of Biomedical
Sciences at BCM. He is a Distinguished Service Professor in the Department
of Molecular and Cellular Biology and serves as co-director of the W.
M. Keck Center for Computational Biology. Dr. Brinkley brings extensive
administrative and research experience to the committee. For example,
Dr. Brinkley was president of FASEB during this funding cycle. Research
in his laboratory involves studies of the structural and molecular bases
of mitosis and genomic instability in eukaryotic cells.
Ralph D. Feigin, M.D. is a professor
and chair of pediatrics, past President of BCM, and Chief of Texas Children’s
Hospital. Dr. Feigin also brings significant research, administrative
and clinical experience to his role as an advisor to the MRDDRC director.
In particular, as the MRDDRC begins to increase its role in translational
research, Dr. Feigin’s advice will be increasingly important.
James W. Patrick, Ph.D. is vice
president and dean of research at BCM as well as head of the Division
of Neuroscience. Dr. Patrick has served on this committee during the
current funding period, and brings expertise in a discipline that has
undergone significant expansion at BCM and within the MRDDRC, as evidenced
by the increasing number of projects in the neurosciences within the
MRDDRC. Basic science advances in the neurosciences will have profound
application in the area of MRDD, and Dr. Patrick’s expertise in
the area will be of significant importance.
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