July 07, 2000
Mutation Can Cause Dangerously High Blood Pressure During Pregnancy
A single mutation in a protein that regulates the body's salt
balance can produce dangerously high blood pressure in pregnant women,
say researchers from the Howard Hughes Medical Institute (HHMI) at Yale
University School of Medicine.
The discovery opens the way to understanding the molecular origins
of a form of hypertension that threatens some eight million pregnant
women and their infants each year.
“This finding has opened the door a crack, giving us a first glimpse of a mechanism underlying hypertension in pregnancy.”
Richard P. Lifton
In an article published in the July 7, 2000, issue of the journal
Science, HHMI investigators Richard P. Lifton and
Paul B. Sigler and colleagues at Yale University and Albert Einstein
College of Medicine report that a mutation renders the
mineralocorticoid receptor more sensitive to progesterone, a hormone
that is produced in abundance during pregnancy. The Science
article is dedicated to the memory of Sigler, who died on January 11,
2000.
When the mineralocorticoid receptor is triggered by aldosterone, its
normal binding partner, it switches on the cellular machinery that
causes kidney cells to reabsorb more salt, ultimately raising blood
pressure. Lifton's group found that when women who have the faulty
receptor undergo the hundred-fold rise in progesterone that occurs
during pregnancy, progesterone overstimulates the receptor, causing
salt retention, expansion of blood plasma volume and skyrocketing blood
pressure.
"Pregnancy-induced hypertension is an important clinical problem,
but nobody has really had a good handle on the biochemical pathways
involved in any form of the disorder," said Lifton. "While our study
certainly doesn't prove the cause of all cases of such hypertension, we
have found the first molecular mechanism by which women can develop
severe hypertension in pregnancy. And that mechanism is an abnormal
link between two normal physiologic pathways."
Despite his team's findings, Lifton remains cautious about
recommending any immediate changes in how hypertension is treated in
pregnant women.
"During normal pregnancy, plasma volume expands substantially. There
has always been concern about giving pregnant women medications that
would decrease their intravascular volume," he said. "This finding
raises the possibility that in a select group of patients with
pregnancy-related hypertension, one might consider a carefully
controlled clinical trial using salt restriction with diuretic
medications." Lifton said that such therapies could first be tested in
a genetically altered mouse that bears a similar mutation in the
mineralocorticoid receptor gene.
Ironically, the research that yielded the new insight into
pregnancy-related hypertension began with a 15-year-old boy. In
sequencing DNA from patients with early-onset hypertension, David
Geller, a research fellow in Lifton's laboratory, discovered that the
boy carried a single mutation in the mineralocorticoid receptor
gene.
"At that point, there was no compelling evidence to suggest that the
mutation actually was the cause of his hypertension," said Lifton.
Thus, the scientists launched both clinical studies of the boy's family
and biochemical studies to pinpoint the effects of the mutation.
In tracing the inheritance pattern of the mutated gene, the
scientists found that all members of the boy's family who had inherited
the mutation had early onset of high blood pressure. And when the
scientists used cell culture studies to compare the activity of normal
and mutant receptors, they found the mutant receptor to be switched on,
even in the absence of a triggering hormone.
"But most surprising was that when we added progesterone, a steroid
that normally binds to, but doesn't activate, the mineralocorticoid
receptor, we found that it was a potent activator of the mutant
receptor," said Lifton. This finding suggested that pregnant women with
the mutant receptor would have completely activated receptors, so
Lifton and his colleagues next examined the medical histories of those
women in the family who had been pregnant.
"When we followed the clinical course of women who had this
mutation, we found that they had developed extremely severe
hypertension in pregnancy," said Lifton. The researchers found that in
all instances the hypertension was so severe that it necessitated
preterm delivery.
Molecular characterization of the faulty receptor by Lifton and his
colleagues revealed a key aspect of receptor activation that is shared
by many related receptors, suggesting a new approach to development of
steroid hormone antagonists.
Lifton also believes that further studies may reveal other defects
that permit normal hormones of pregnancy to activate the salt
reabsorption machinery and cause hypertension. "This finding has opened
the door a crack, giving us a first glimpse of a mechanism underlying
hypertension in pregnancy," said Lifton. "Knowing that one form of
pregnancy-related hypertension can be caused by the abnormal action of
a normal hormone, raises the question of whether other forms of
hypertension act by a similar mechanism. There's still a long research
path to be followed before a disease as complicated as hypertension is
understood in satisfactory detail."
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