August 20, 1995
Genes or Environment? Researchers Probe Sudden Death
A mouse model of familial hypertrophic cardiomyopathy (FHC) is
providing scientists with valuable information about whether genes or
environment trigger sudden death.
FHC is a devastating disease that kills people in the prime of life
with very little warning. Over a period of years, the heart wall of
those with FHC thickens to an abnormal degree, and death can result
from vigorous exertion or prolonged stress on the heart. Some with FHC
die even though there is no apparent triggering event.
“We are now in a much better position than before to examine background factors that might also control the severity of this disease. Such information could one day be extremely useful when making recommendations to patients about how they should live their lives.”
Jonathan G. Seidman
During the past decade scientists have made remarkable progress in
uncovering the genes associated with the disease. They know, for
instance, that FHC can be caused by many different mutations in
contractile proteins that make up the heart wall. Such genetic
information has made possible a blood test to detect the presence of
faulty genes in people who have a family history of sudden death. And
researchers have had success in studying those mutations to predict the
severity of the disease. But they are still a long way from knowing who
will die suddenly or whether factors like high blood pressure or
extreme stress will trigger sudden death.
A group of geneticists and cardiologists at HHMI at Harvard Medical
School and Brigham and Women's Hospital in Boston have now developed a
mouse model of FHC that should greatly enhance genetic studies of the
disease. In the past, animal models of hypertrophy (thickened heart
wall) have been available, but none is a mirror of FHC in humans, said
project leader Jonathan Seidman, a Hughes investigator at Harvard
Medical School.
Seidman and his wife, Christine E. Seidman,
a Hughes investigator at Brigham and Women's Hospital, reported in
Science that they have bred mice with single point mutation in
the gene for myosin, a muscle protein found in the heart. Using
embryonic stem cell technology, the researchers changed a single
nucleotide in the myosin gene from arginine to glutamine, and then bred
mice that matured with the mutation in their genes. "We selected this
particular mutation," said Jonathan Seidman, "because we knew from our
work with FHC families that individuals with this mutation have a
relatively short life expectancy."
Mice with mutations in both copies of the myosin gene died within
seven days of birth. Those mice with one altered myosin gene lived one
to two years before dying, a life expectancy that reflects human
FHC.
One of the most important features of the mouse model of FHC is that
it will now allow the Seidmans to study to what extent genetics or
environment influences FHC. For example, the scientists can now subject
mice to strenuous exercise and see how that exertion affects the size
of the heart muscle wall. Likewise, they might wish to breed FHC mice
with alterations in genes that control blood pressure and see if those
genes have an impact on survival. "We are now in a much better position
than before to examine background factors that might also control the
severity of this disease," said Jonathan Seidman. "Such information
could one day be extremely useful when making recommendations to
patients about how they should live their lives."
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