Master Switch:
In `Tinman' Gene,
Scientists See Root
Of 2 Heart Defects
DNA Glitch Causes a Flaw In Babies, Then in Adults
The Appels' Misfortune
A Fruit Fly's Scientific Trail
By Ron Winslow
The Wall Street Journal
7/29/04
BATTLE GROUND, Wash. -- Eileen Appel and five members of her
family, spanning four generations, were born with holes in their hearts.
Each underwent surgery to patch up the hole and thought it was
fixed. Years after the operations, her mother at age 48 and then her
two sisters at 49 and 52 died. Just three years ago, her 35-year-old
son succumbed as well. In each case, their hearts stopped without
warning -- sudden cardiac arrest. Ms. Appel, 61, and her grandson Matthew,
20, both have had close calls. They now depend on devices implanted in
their chests to keep the rhythm of their hearts under control. "We always knew there was something in our makeup that was
wrong," Eileen says.
Scientists now have a name for it: a defect in a gene called
Tinman. To the surprise of cardiologists, the same genetic flaw that caused
the birth defect in all of the Appels also appears responsible for
aberrant heartbeats decades later that can lead to heart failure and
sudden death. The discovery of Tinman demonstrates a principle that scientists
are encountering more and more as they pore over the genetic code of
living things. "What we're learning is that Mother Nature has a
limited repertoire of genes that can make organs," says Bruce Gelb,
co-director of the cardiovascular genetics program at Mount Sinai School of
Medicine in New York. "So she tends to use them for more than one aspect
of development."
The identification of the Tinman gene also illustrates the
interplay between basic research and patient care. The chance discovery of
an unusual fruit fly in Michigan first put scientists on the trail of
a culprit in heart defects, but it took careful observation of
families such as the Appels to pinpoint that culprit's whereabouts.
So far, the work offers only limited benefits for people with
Tinman mutations. Scientists are looking at potential targets for drugs
that might alleviate effects of the mutation, although any treatment
is probably many years off.
About one in every 125 babies is born with a structural anomaly in
the heart. The heart has four chambers: two atria and two ventricles.
People such as the Appels have atrial septal defects -- a hole in the
wall, or septum, dividing the two atria of the heart. Other anomalies
include a septal defect of the ventricles and a quartet of defects known
as tetralogy of Fallot. In about two-thirds of cases, the holes in
the septum heal on their own. But if they don't, they can sap energy,
damage the heart muscle and lead to heart failure.
Today, thousands of children each year undergo hospital procedures
to repair their abnormalities. Since the operations were first done
in the early 1950s, advances in technology and technique have made it
possible to patch up the holes without open-heart surgery in many cases.
The procedures are an important reason why about one million Americans
born in the last three decades with congenital heart defects are alive
today.
For years, doctors have assumed that the repair was a cure. But
over the past decade, cardiologists have been seeing some patients
whose experience resembles that of the Appels. These patients had their
hearts patched up during childhood and now are suffering new problems in
their 20s and 30s, including heart-rate anomalies serious enough to
require pacemakers and defibrillators. What's odd is that these problems
usually involve the electrical signals that make the heart beat, not
some leftover structural problem from the original surgery.
"There is a subset of patients where just having the surgery
doesn't mean you're out of the woods," says Kenneth R. Chien, head of
the Institute of Molecular Medicine at University of California at
San Diego.
A recent Dutch study of 135 patients who had atrial septal
defects repaired during childhood found that 8% had an irregular heart
rhythm after an average of 26 years of follow-up, and 5% required
pacemakers. A Canadian study published in 2001 tracking 242 patients with repair
of the tetralogy of Fallot defects found that 29, or 12%,
developed sustained heartbeat abnormalities later in life.
These long-term problems probably aren't caused solely by a single
gene defect. Scars from surgery or a repair delayed beyond early
childhood may raise the risk, cardiologists say, as can the role of
other heart-related genes.
Commercial tests to detect the genes that might put someone in
the high-risk subset aren't available, so it's hard for doctors to
pinpoint the risk for a patient who had a heart abnormality repaired. Those
with a family history of heartbeat irregularities and sudden death are
at highest risk and should be regularly monitored, cardiologists
say.
The heart is the first organ to form after conception, emerging by
the seventh week as a four-chambered structure. The right side of the
heart receives oxygen-depleted blood from the body and pumps it to the
lungs. The left side takes fresh oxygenated blood from the lungs and
pumps it to the rest of the body.
Because a fetus has its blood oxygenated by the mother's lungs, a
small hole normally remains in the septum to let blood circulate
efficiently through the fetal heart. Then, what Deepak Srivastava of the
University of Texas Southwestern Medical Center describes as a "trap door"
closes the hole around the time of birth.
Scientists believe this process is governed by a group of genes
called transcription factors. They act like master switches, turning
immature cells into specific parts of the heart. If the genes are
defective, so is the heart's development.
In the late 1980s, Rolf Bodmer, a neuroscientist then at the
University of Michigan, was examining fruit-fly genes in an effort to find
master switches in the nervous system when he happened to find one that
seemed active in the heart instead. Rather than cast it aside, he pursued
the lead and eventually was able to observe embryos of fruit flies
that lacked the gene. They didn't have a heart. He called the gene
Tinman, after the Wizard of Oz character who lamented his lack of a
heart.
A fruit fly heart is little more than a tube that circulates
fluid around the body cavity. But soon after Dr. Bodmer published
his discovery in 1993 other scientists found a corresponding gene in
mice. By 1995 Australian researchers created a mouse without the gene. Such mice began to develop a heart in the uterus but it failed to
progress into a four-chambered organ. The mouse fetuses died.
This led scientists to wonder whether Tinman existed in humans,
and if so what its role was. A husband-and-wife team at Harvard
discovered a surprising answer. In the mid-1990s, Jonathan and Christine
Seidman started looking for families that shared a history of heart
defects. They found a medical article from the 1970s that described a
family in Pennsylvania in which 12 people over five generations had heart
defects at birth, heart problems later in life or both. The Seidmans
tracked down the article's author, who had retired, and through him the
family. The Seidmans took blood samples from the Pennsylvania family but
figured data from additional families would make their results more
solid. That's when the Appel family with its history of heart problems
entered the picture.
Eileen Appel was 14 and living in Los Angeles when she had a hole
in her heart repaired. It was 1957, and she was told her chances of
surviving surgery were 50-50. Her older sister had gone through it three
years earlier. After their mother had the operation in 1960 at age 40,
the three of them were featured in a local newspaper article as
"boosters" for the annual Los Angeles County Heart Association fund drive.
Eileen Appel's younger sister got the operation a few years later.
Their mother died suddenly in 1966, just 11 months after Eileen's
son, Dennis, was born and discovered to have a heart murmur. Eileen,
who worked as an administrative assistant in a government office,
didn't have a symptom for 21 years following her surgery. One day in
1978, she began seeing black spots and stars while sitting at her desk at
work. She went to the hospital in an ambulance and came out with a
pacemaker in her chest.
"My sisters called me `bionic' and said I was paranoid about my
health," she recalls. She had her pacemaker checked every year. Her
sisters smoked and had high blood pressure, but never had pacemakers
installed. They both died suddenly -- the older sister in 1990 and the
younger sister in 1997 at age 52.
A doctor in Portland, Ore., who did an autopsy on the younger
Appel sister mentioned the string of misfortune to Michael Silberbach,
a pediatric cardiologist at Doernbecher Children's Hospital and
Oregon Health and Science University in Portland. He had a friend who
was working with the Seidmans at Harvard. Through that link, Eileen
Appel was asked if her family wanted to join the Seidmans' study. She
agreed, eager to know what was plaguing her family.
By 1998, the Seidmans had blood samples from more than 30 heart
patients like the Appels and a similar number from family members without
any heart problems. When all the samples were compared, it was a
eureka moment. The people with heart problems all had mutations within
a certain section of chromosome No. 5 of their DNA -- the place
scientists had mapped the human version of Tinman, which is called Nkx2.5.
Further analysis confirmed the gene as the culprit. These people had
inherited one defective copy of Tinman and one normal copy from their
parents.
By looking at what happened to the Appels and the other
families, scientists concluded that the gene had a dual function: Before
birth it directed the development of the heart, and after birth it
maintained the electrical system that regulates heartbeats. The findings were
published in the journal Science in 1998.
The next step was to figure out what was going wrong in the adults
whose hearts were failing to beat properly due to the defective Tinman
gene. A heartbeat is triggered by an electrical signal that causes first
theatria to contract and then the ventricles. If the signals get mishandled, the
contractions can go out of sync, forcing the heart
to work harder and increasing the risk of irregular beats, heart
failure and ultimately sudden death.
Mice with one mutated copy and one normal copy of Tinman -- the
same as the people studied by the Seidmans -- would have been a natural
model to study the electrical malfunction, but researchers hadn't found
any obvious defects in such mice. At the University of California at
San Diego, Dr. Chien had another idea. He engineered a mouse in which
the Tinman gene was removed only in heart ventricle cells. The idea
was to let the heart develop normally at first but disable the gene
before it started playing its role in the heart's electrical system. Within 12 weeks of birth, the mice began to have irregular heart
beats.
Their ventricles became abnormally enlarged, reflecting "a growth
switch that was turned on and never turned off," Dr. Chien says. And
the atrioventricular node -- a key switch that controls the movement
of the electrical signal through the heart -- was small and abnormally
shaped.
What wasn't known was what a Tinman mutation looked like in the
human heart. Once again, it was time for the Appels to make a
contribution to science.
One morning in 2001, Eileen's son, Dennis, raised himself from his
bed on his elbows, tried to say something to his wife, coughed and
slumped down on the bed. "It happened in a matter of seconds," says his
wife, Vicki. "There were no signs." By the time paramedics arrived it
was too late to revive him.
Dr. Silberbach in Portland asked the Appels for Dennis's heart.
With their permission, he sent it to a pathologist in London along with
the heart of one of Eileen's deceased sisters, which he had
previously collected. The London pathologist found the left ventricles of the
two hearts were substantially enlarged and the atrioventricular nodes
were barely recognizable. Since the node is at the center of the
heart's electrical signaling, that almost certainly contributed to the
two Appels having died suddenly.
Around that time, Dr. Chien of UC San Diego came to Oregon to
givelectures. He met with Dr. Silberbach and the two men discovered
their mutual interest in Tinman. When Dr. Chien described the impact of
the gene on the electrical systems of his mice, Dr. Silberbach replied
that the effect on human hearts was the same. "It was a key moment,"
Dr. Chien says. "There's always a danger when you work with mice that
the molecular mechanisms will be different than they are in humans."
The two men agreed to incorporate the pathology findings on the Appels'
hearts into a paper that Dr. Chien and his colleagues were preparing. The
paper appeared April 30 this year in the journal Cell.
For all the progress, Eileen Appel and her grandson, Matthew,
don't havea cure for their heart conditions. Eileen has a pacemaker that
regulates her heartbeat while Matthew has a combination pacemaker and defibrillator to maintain a regular heartbeat and protect his
heart from racing out of control or stopping. "I'm a normal person," says
Matthew, who works at an electronics store. "If I could get rid of it, it
would be great."
Further down the road is the potential for drug treatment. Dr.
Chien has found that Tinman mutant mice had as much as 500 times the normal
level of a growth factor called BMP-10 (for bone morphogenic
protein-10). He wonders whether BMP-10 is causing heart tissue to proliferate excessively -- and if blocking BMP-10 through some yet-unknown
drug could prevent at least some damage to the heart's electrical
system.
It's too early to know whether that will pan out, but
researchers believe that further studies of genes that control the heart's development will lead to targets for drugs. "People wonder why we study fruit flies, worms and zebrafish,"
says Dr. Silberbach. "Here, you've taken a gene you've found in a simple
life form and identified it as a cause of important disease in humans.
Then you study the mechanisms of the disease by recreating it in a
mouse. It is a model for how the ideal genetic research should go."
(Copyright (c) 2004, Dow Jones & Company, Inc.)
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