Johns
Hopkins Medicine
Media Relations and Public Affairs
Media Contact: Audrey Huang
410-614-5105;
audrey@jhmi.edu
October 5, 2006
PRESS RELEASE
Johns Hopkins researchers have
teased out the function of a protein implicated in
Williams-Beuren syndrome, a rare cognitive disorder
associated with overly social behavior and lack of spatial
awareness. Called TFII-I, or TF “two eye,” the protein long
known to help control a cell’s genes also controls how much
calcium a cell takes in, a function critical for all cells,
including nerves in the brain. The study will be published
this week in Science.
“While the previously described
function of TFII-I very well also could contribute to the
cognitive defects of Williams-Beuren syndrome, its role
controlling calcium makes much more sense,” says Stephen
Desiderio, M.D., Ph.D., a professor of molecular biology
and genetics and director of the Institute of Basic
Biomedical Sciences at Hopkins. And, says Desiderio, others
have shown that defects in a cell’s ability to take in
calcium can lead to other neurological and behavioral
conditions.
Williams-Beuren syndrome is
associated with craniofacial defects, problems with the
aorta and a very specific mental retardation that causes
those affected to be talkative, sociable and empathetic but
at the same time have significant spatial learning defects.
Those affected are highly expressive, have exceptionally
strong language abilities and “can talk up a storm,” for
example. But at the same time, they are poor at global
organization, having problems re-creating patterns in
drawings. The syndrome occurs in roughly one in 25,000
births and is caused by a deletion of a small section of
chromosome 7 that contains several genes, including the
gene that encodes the TFII-I protein.
The discovery came after
Desiderio and his team used biochemical “bait” to fish for
candidate proteins that physically bind to TFII-I. The
fishing expedition returned one protein known to control
when and how much calcium a cell takes in.
“The partner we found in the
fishing experiment and the abundance of TFII-I outside the
cell nucleus led us to suspect that this protein must be
doing more than regulate gene expression,” says Desiderio.
Under normal conditions, calcium
does not flow freely into and out of cells until a demand
for it - such as a muscle contraction or nerve function --
triggers cells to take up the free floating element from
their surroundings. Cells store calcium until still other
signals occur to release it again.
“The finding was stunning to us
because calcium is one of the most important messengers in
cells,” says Desiderio, “and both it and TFII-I are in
every cell. That affirmed our suspicion that TFII-I could
be doing something important with calcium signaling.”
In one experiment, the Hopkins
team knocked down the amount of TFII-I in lab-grown cells
and looked for changes in calcium flow under a high-power
microscope using a dye that glows when it comes in contact
with calcium. A camera attached to the microscope recorded
the brightness of the glow and fed that measure into a
computer that calculates the amount of calcium.
Knocking down TFII-I and
separately assaulting the cells with chemicals caused the
cells to take up more calcium than usual.
The researchers realized that
when they depleted the cells of TFII-I, the cell responded
by installing more calcium channels in their surfaces that
allow calcium and only calcium to enter the cell. “We think
TFII-I must control calcium entry into the cell by somehow
limiting the number of calcium channels at the cell’s
surface,” says Desiderio.
“There’s good evidence
suggesting that the frequency and intensity of this ebb and
flow of calcium can determine a cell’s response to external
cues,” says Desiderio. “TFII-I may be a universal player in
communication between cells, in the brain, the immune
system and elsewhere.”
The researchers were funded by
the Howard Hughes Medical Institute, the National Cancer
Institute and the Institute for Cell Engineering at
Hopkins.
Authors on this paper are
Gabriela Caraveo, Damian van Rossum, Randen Patterson,
Solomon Snyder and Desiderio, all of Hopkins.
On the Web:
http://www.mbg.jhmi.edu/FacultyDetails.asp?PersonID=363
http://www.hopkinsmedicine.org/ibbs/index.html
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