October 01, 2004
Researchers Pinpoint Cause of a Severe Cardiac Arrhythmia
Howard Hughes Medical Institute researchers have pinpointed the
genetic cause of a devastating but rare childhood disorder, called
Timothy syndrome, which underlies a form of severe cardiac
arrhythmia.
The research shows that the syndrome results from spontaneous
genetic mutations that interfere with calcium channels that regulate
the excitation and contraction of the heart. In defining the precise
nature of the molecular abnormality, however, the researchers have also
identified a class of drugs that they hope will alleviate the
arrhythmia.
“At that point, we only knew we were dealing with a severe arrhythmia of a type we had not seen before.”
Mark T. Keating
Timothy syndrome may also cause a form of autism in those affected,
and there is the possibility that understanding more about the nature
of these calcium channel defects could improve understanding of autism,
which affects 200,000 to 400,000 children in the United States. Calcium
channels are pore-like proteins that nestle in cell membranes and
control the flow of calcium into and out of the cell. Calcium is one of
the most important signaling molecules in the body, and perturbing
calcium transport can cause a wide range of disorders.
Howard Hughes Medical Institute investigator Mark T. Keating and his
colleagues reported in the October 1, 2004, issue of the journal
Cell, that a pinpoint mutation in the CaV1.2 calcium
channel was the sole cause of Timothy syndrome. Keating collaborated on
the studies with researchers from Children's Hospital, Boston, Harvard
Medical School, the University of Utah, the University of Pavia in
Italy and the Boston University School of Medicine.
The scientific path that led to the identification of the cause of
Timothy syndrome began in 1989 with the identification of a single
child with the then nameless disorder by Katherine W. Timothy of the
University of Utah. That child presented with cardiac arrhythmia and a
webbing, or syndactyly, of the hands and feet - characteristics of what
has now come to be called Timothy syndrome in honor of Katherine
Timothy's long and distinguished career as a scientist
investigating the causes of cardiac arrhythmias, said
Keating.
Timothy knew that Keating, who was at the University of Utah at the
time, had a longstanding interest in arrhythmias, so she began
collaborating with him to understand the disorder. Tragically, the
first child died quickly, so the scientists were unable to explore the
effects of the disease in that patient.
“At that point, we only knew we were dealing with a severe
arrhythmia of a type we had not seen before,” said Keating.
“But as we were able to treat these children more successfully,
it became clear that they had other problems, including congenital
heart disease, intermittent hypoglycemia, cognitive abnormalities and
autism.”
The researchers then began the laborious process of attempting to
trace the genetic cause of the disease. Familial studies revealed that
it was not inherited, but caused by a mutation that occurred
spontaneously. Eventually their analyses of a multitude of genes
revealed that in all the patients, the disorder was caused by a change
in a single DNA unit, or nucleotide, in the CaV1.2 calcium
channel.
“This channel was known to be important for the excitation and
contraction of the heart, but its role in other parts of the body were
less clear,” said Keating.
Studies of the pattern of activity of the gene for the channel in
humans and mice revealed that it was expressed not only in heart muscle
cells, but also in adult and fetal tissues of the brain,
gastrointestinal system, lungs, immune system, smooth muscle and
testis. In particular, said Keating, mouse studies showed the gene to
be active in brain regions that were known to show abnormalities in
autism.
Cell culture studies of the mutated version of the channel revealed
that it did not react properly to block calcium flow at the appropriate
time. This abnormality could explain the lethal cardiac arrhythmias in
Timothy syndrome patients, said Keating.
Further genetic analyses of the particular mutation also showed why
it occurred in the same place in all instances of the disease. That
analysis revealed that the particular site of the mutation was a
hotspot in the genome that was more prone to spontaneous mutation, said
Keating.
“With these findings, we had a good handle on why this
particular mutation would cause an arrhythmia and also how we could
reduce the risk of arrhythmia in these children by blocking that
channel,” said Keating. The investigators hope that
calcium-channel-blocking medications may reduce arrhythmia and improve
cognitive function in this disorder.
“While there are developmental abnormalities that we can't
treat, it is very gratifying for us and for the families of these
children that we may be able to deal with some of their physiological
abnormalities,” said Keating.
According to Keating, discovery of the genetic basis of Timothy
syndrome has implications for understanding the function and importance
of calcium channels in general. “Our findings showed that the
mutated region is required for inactivation of the channel, which was
not previously appreciated,” he said. “More broadly, this
finding really highlights in a way that I haven't seen before the
fundamental importance of calcium metabolism in development and
physiology in humans.”
While Keating emphasized that autism remains a deeply mysterious and
complex disorder, “it certainly is a reasonable hypothesis that
abnormal calcium signaling could contribute to the disorder in some
cases,” he said.
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