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DURHAM, N.C. -- An international team led by researchers
from Duke University Medical Center and the Howard Hughes
Medical Institute (HHMI) have demonstrated a genetic basis for
a fatal form of inherited cardiac arrhythmia that usually
strikes young, seemingly healthy people.

The results of the study were published in the Feb. 6, 2003
issue of the journal Nature.

Basing their research on a French family with a form (Type
4) of inherited Long QT Syndrome (LQTS) and experiments in
mice, the researchers found the mutation in a specific gene
encoding ankyrin-B, a protein within heart muscle cells. Their
discovery identifies what appears to be a novel mechanism for
cardiac arrhythmia.

Normally, ankyrin-B acts as a biochemical symphony
conductor, ensuring that microscopic pores in heart muscle
cells known as ion channels open and close in a coordinated
fashion. These channels allow such chemicals as calcium,
potassium, sodium and chloride to pass in and out of the cell
with each heartbeat, thereby regulating the electrical activity
of the heart.

"We have found a brand new mechanism for cardiac arrhythmias
based on the coordination of these different ion channels,"
said HHMI investigator and Duke cell biologist Vann Bennett,
M.D., senior member of the research team. "It appears now that
the arrhythmia arises, not due to some malfunction of the ion
channels themselves, but a failure to ensure that multiple ion
channels open at the right place and at the right time.
Scientists have been looking for ion channel mutations, but
they have not been able to find them."

The QT interval is a measurement taken by electrocardiogram
that represents the period of time from electrical stimulation
of the heart's pumping chambers to their recharging for the
next heartbeat. In normal people, this interval ranges from
0.38 to 0.44 seconds. However, for people with LQTS, this
period of recharging can be delayed up to 0.5 seconds, which
put these patients at high risk for arrhythmias.

This constant back-and-forth electrical stimulation and
recharging is controlled by different ions passing in and out
of the cell, which alternately changes the cell's polarization.
About one-third of patients with the disorder never experience
symptoms, but those who do can experience loss of
consciousness, abnormal heartbeats or sudden death.

LQTS is a dominant genetic disorder, meaning that each child
of a parent with the disorder has a 50-50 chance of getting the
disease.

In 1995, the researchers identified a large family in France
with a preponderance of members with LQTS. A specific mutation,
known as E1425G, was found to be associated with LQTS in 22 of
24 of the family members and with abnormal heart rhythms in 23
out of 24 members. The mutation was not present in more than
400 control samples.

The researchers then examined effects of this mutation on
the important ion channels that regulate calcium levels in
heart cells using their ankyrin-B mutant mouse model of
LQTS.

"We found that two normal copies of the ankyrin-B gene are
necessary for normal calcium signaling, and that the E1425G
mutation leads to a loss of function," said Peter Mohler,
Ph.D., HHMI post-doctoral fellow at Duke and first author of
the paper. "So, ankyrin-B is the first identified protein
implicated in a congenital LQTS that is not an ion
channel."

The team performed further comparisons between humans with
LQTS and mice with the E1425G mutation of ankyrin-B, and found
striking similarities in cardiac performance, including reduced
heart rate, a high degree of heart rate variability and other
heart rate disturbances that could not be linked to electrolyte
or structural defects of the hearts. They also found similar
loss of function in ion channels other than calcium.

"Sudden death in humans with this mutation usually occurred
after physical exertion or extreme emotional stress," Mohler
said. "One of the members of the French family died suddenly at
the age of 37 while running up a hill. So we wanted to see if
this same effect would be present in the mouse models."

To simulate these circumstances, the researchers exercised
the mice and then injected them with epinephrine, one of the
so-called "fight-or-flight" hormones that stimulate the
heart.

"Of the 14 mice with the mutation, two became unresponsive
seconds after exercise, and eight died following exercise
combined with the injection," Mohler said. "The effect was
dramatic. None of the mice without the mutation showed any
adverse effects from the exercise or the epinephrine."

Bennett believes that the insights gained in these
experiments could also have important implications for
disorders of other organs, especially those that like the
heart, have excitable membranes responsible for proper organ
function. These organs include the nervous system, the lining
of the lungs and the kidneys, and beta cells in the pancreas
that are responsible for release of insulin.

The research was supported by the National Institutes of
Health, the Muscular Dystrophy Association, the Canadian
Institutes of Health, the Institut National de la Sante et de
la Recherche Medicale, and the Programme Hospitalier de
Recherche Clinique.

Other members of the team are: Jean-Jacques Schott, Karine
Haurogne, Florence Kyndt and Denis Escander, Laboratoire de
Physiopathologie et de Pharmacologie Cellulaires et
Moleculaires, Hotel-Dieu, France; Herve Le Marec, Hospital
G&R Laennec, Nantes, France; Keith Dilly, Silvia
Guatimosim, William H. duBell, Long-Sheng Song, Terry Rogers
and W.J. Lederer, University of Maryland; and from Duke,
Anthony Gramolini and Mervat Ali.