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COLLEGE STATION, TX - Dr. Scott Dindot,
assistant professor in the Veterinary Pathobiology department at
the Texas A&M University College of Veterinary Medicine &
Biomedical Sciences (CVM) has been awarded a research grant
totaling about $100,000 for Angelman syndrome (AS) research.
AS is a moderately rare disorder, affecting 1 in 12,000
individuals in the United States. It is characterized by mental
retardation, speech impairment and motor dysfunction. It is caused
by the absence or loss of function of the maternal copy of the
UBE3A gene, which is present on chromosome 15 in humans. This gene
encodes a protein called E6-AP. However, how the absence of this
protein leads to the syndrome's clinical manifestations is not
As a step toward resolving this puzzle, Dindot is working on
determining the function of this protein.
The one-year grant awarded by the Angelman Syndrome Foundation
will fund a project Dindot will begin in January 2010 at the
The project will be the continuation of a study Dindot worked on
as a postdoctoral researcher at the Baylor College of Medicine. In
this study, his research group showed that the E6-AP protein may be
essential for the normal development of nerve structures called
Dendritic spines are components of synapses (or synaptic
connections), which are junctions through which neurons (or nerve
cells) communicate with each other.
It is believed that changes in the number, size and shape of
dendritic spines affects cognitive functions, such as learning and
memory, through a process called synaptic plasticity.
"As we learn, as we add information to our brain, we strengthen
synaptic connections [this process is called synaptic plasticity],
which is manifested by dendritic spines becoming larger," Dindot
Dindot's previous study showed that in adult models of mice with
AS (that did not produce the protein E6-AP in their neurons),
dendritic spines were immature in morphology and number. Also, in
mice without the syndrome, E6-AP was observed to be present in
Taken together, these findings indicated that E6-AP plays a role
in dendritic spine development.
The focus of Dindot's upcoming project will be on determining
which of the three isoforms of the human E6-AP protein is
associated with dendritic spine development.
"We will culture hippocampal neurons [which are involved in
learning] from Angelman syndrome mice," Dindot said, explaining the
experimental method of the project. "Then, we will express each of
the three isoforms of the human E6-AP protein in these cultured
neurons and see which isoform of the protein can rescue or fix the
dendritic spine defect in these mice."
According to Dindot, identifying which isoform of the E6-AP
protein is associated with the dendritic spine defect can form the
theoretical basis of some sort of therapeutic intervention for this
disease, for example, gene therapy [replacing the defective UBE3A
gene with a normal gene] or developing drugs that induce the
expression of the E6-AP protein.
"What makes the E6-AP protein so important," Dindot said, "is
that the gene that encodes it [that is, UBE3A] is a major player in
neurodevelopmental disorders." He explained how this gene is
involved in not only AS but also autism.
"Chromosome 15q duplication syndrome is the duplication of the
UBE3A gene and the region on the chromosome in which it is present.
When this defect is maternally inherited, it is the most common
cytogenetic abnormality associated with autism. So not only does
UBE3A give rise to AS when absent, when it is present in excess,
presumably it gives rise to autism."
Another reason for Dindot's interest in AS is that it is a
disorder that involves "genomic imprinting" and "epigenetics," two
genetic phenomena he has been curious about since his PhD days.
"Angelman syndrome arises only through mutations [caused by
changes in the DNA sequence of a gene] or epimutations [caused by
changes in epigenetic modifications] inherited from the mother,"
Dindot said. "When these mutations are inherited from the father,
there is either no disorder or a completely different disorder
called Prader-Willi syndrome. This is due to a phenomenon called
genetic [or genomic] imprinting."
Dindot elaborated on the epigenetic cause of the syndrome.
"Epigenetics has to do with the regulation of genes," he
explained. "There are kids with AS that have no genetic mutation
altogether. But instead they have abnormal epigenetic modifications
at a regulatory element responsible for driving the expression of
the [UBE3A] gene, which turns the gene off. So you end up with the
Angelman syndrome despite not having a mutation in the UBE3A
Commenting on the broader scope of his research, Dindot said
that his lab is interested in "studying the epigenetic regulation
of the gene that causes Angelman syndrome."
Grateful for being selected as one of the six recipients of
grants awarded by the Angelman Syndrome Foundation this year for
research on this disorder, Dindot said that the funds will be used
for purchasing reagents and building his team. In the end, he hopes
that his work will be a step toward achieving the goal of the
foundation, which is to find a cure for this disease.
Angela G. Clendenin
Director, Communications & Public Relations
Ofc - (979) 862-2675
Cell - (979) 739-5718
Texas A&M University, College Station, Texas 77843
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