May 01, 1995
Sodium channel gene key to high blood pressure of Liddle's syndrome
High blood pressure is a malady some Americans acquire as a consequence of many
factors, including genetics, diet and age. The broad range of components
involved have made it extremely difficult for scientists to pinpoint which
faulty genes might cause blood pressure to inch skyward.
So it is particularly instructive when researchers stumble across a family in
which high blood pressure is an inherited trait. In 1963, Grant Liddle, a
physician at Vanderbilt University, found a Tennessee family in which several
of the members had extremely high blood pressure and low potassium levels.
“It's as if the flood gates to a dam have been left open and can't be closed. These patients are always retaining too much salt and water.”
Richard P. Lifton
Liddle's work suggested that people in this family could not maintain the
proper balance of salt and water in the body. Their chemical imbalance created
the alarmingly high blood pressure that is the cardinal feature of what came to
be called Liddle's syndrome.
Thirty-one years after Liddle's seminal observations, researchers with the
Howard Hughes Medical Institute at Yale University led a team that found the
genetic cause at the heart of Liddle's syndrome. The group reported in the
November 4, 1994 issue of
that an abnormal sodium channel gene in
the kidney causes the body to retain excessive amounts of salt and water, which
leads to high blood pressure.
"These findings are useful to families with this rare disorder," said
, an HHMI
investigator at Yale. "Moreover, this work raises the possibility that
more subtle mutations in this same gene may contribute to more common forms of
high blood pressure. Finally, these mutations reveal the presence of a novel
mechanism regulating sodium reabsorption."
Since the early 1960s, Liddle's syndrome has remained an interesting sideline
in the field of hypertension research. The rarity of the disorder had precluded
scientists from obtaining enough blood samples for serious molecular study of
the syndrome. Lifton tried to track down members of the family Liddle used in
his original study; however, "it was as if the family had vanished,"
In 1991 his luck began to change. A chance encounter with David Warnock, a
kidney specialist at the University of Alabama, Birmingham (UAB), led to the
news that one of the members of the family in Liddle's original study had
developed renal failure and had just undergone a kidney transplant at UAB.
"That this family just resurfaced after 28 years was incredible
luck," Lifton said.
Lifton and Warnock agreed that genetic approaches might finally pin down a
cause of the high blood pressure. They were pointed in the right direction by a
scientific paper by Drs. Cecilia Canessa and Bernard Rossier of the University
of Lausanne in Switzerland, who reported cloning genes responsible for sodium
reabsorption in the kidneys of rodents.
Lifton's group surmised that mutations in the corresponding genes in humans
might be the cause of Liddle's syndrome. Richard Shimkets, a Ph.D. candidate at
Yale whose graduate work is supported by HHMI, tested that hypothesis and found
a mutation in the same part of the sodium channel in every clinically affected
member of the family Liddle had originally studied.
Further studies of four more affected families confirmed similar mutations in
all of these patients. "It's as if the flood gates to a dam have been left
open and can't be closed," Lifton said. "These patients are always
retaining too much salt and water."
The new findings provide the basis for a genetic test which permits people with
this disorder to be identified earlier and then treated with the proper
medications. Lifton is hopeful that the work will shed light on the more common
causes of high blood pressure, a disease that affects 50 million Americans and
kills about 200,000 annually.