By David N. Leff

Pregnancy can be hazardous to a woman's health, and life - if she carries a recently identified gene mutation. It encodes a flawed form of the receptor for a steroid hormone called mineralocorticoid.

"So when women who carry this mutation become pregnant," observed molecular geneticist Richard Lifton, of the Howard Hughes Medical Institute at Yale University, "they develop severe hypertension, because a normal hormone of pregnancy, progesterone, now has an abnormal action. It normally acts as an antagonist of the mineralocorticoid receptor [MR], which promotes salt and water reabsorption in the kidney. But as a consequence of this mutation," he continued, "it now has the opposite effect. It acts as an agonist, and promotes massive salt and water retention, leading to very severe high blood pressure.

"In general," Lifton continued, "pregnancy-induced hypertension affects 6 percent of all pregnancies, an incidence believed to be fairly consistent worldwide. So that would be about 8 million pregnancies a year. The disorder," he said, "contributes to morbidity and mortality in both the mother and fetus to a degree that depends largely on its recognition and treatment. If untreated, it can cause serious medical complications, including eclampsia, which is potentially fatal.

"Even in the non-pregnant state," Lifton added, "this MR mutation causes hypertension. But when a woman becomes pregnant and her progesterone levels go up, the hypertension becomes pretty much impossible to manage. It has proved maddeningly difficult to figure out the primary causes of pregnancy-induced hypertension.

"The disorder," he said, "is inherited as an autosomal dominant trait. So everybody we studied who inherited this mutation developed significant hypertension before the age of 20, which is an unusual, early-onset feature in the general population."

Lifton is senior author of a paper in the current issue of Science, dated July 7, 2000. Its title: "Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy."

"This represents a first link," he told BioWorld Today, "between a normal pregnancy change in physiology that when it goes wrong causes this severe form of the pregnancy disorder. I think its importance is that it naturally raises the question of whether other abnormalities in the same part of the biochemical pathway of salt reabsorption in the kidney might underlie more common forms of pregnancy-related hypertension."

Salt Balance Tutorial 101

To explain this link, Lifton resorted to analogy: "How much water can you squeeze into a garden hose if the hose is analogous to your blood vessel? If you pump more water into the hose, you can see that the pressure is going to go up. And that's in essence what happens with this disease. You reabsorb more salt, water is reabsorbed to maintain a constant concentration of sodium in the bloodstream - which is important for neural function - and blood pressure rises as a consequence. So if you change the balance, increase your intake of salt and water, the pressure goes up. Decrease salt and water, blood pressure goes down.

"Our bodies have a set point for salt balance," Lifton noted. "We eat variable amounts of salt, drink variable amounts of water, and yet we have to be pumping blood, delivering oxygen and nutrients to the tissues, in adequate amounts all the time. The body has a very elegant homeostatic mechanism for maintaining intravascular volume to permit adequate perfusion of tissues at all times. This regulates how much salt and how much water the kidney reabsorbs from what it filters all the time.

"The kidney in a normal day filters 170 liters of plasma. So it precisely regulates how much of the salt and water gets reabsorbed and returned to the bloodstream. If you're eating a ton of salt and drinking a lot of water, the kidney says, 'Let that go; I don't need it to maintain normal balance.' On the other hand, if you're hiking in the desert and don't have access to water, the kidney recognizes that you're becoming dehydrated, and reabsorbs every molecule of sodium and water that it can lay its hands on.

"What happens as a consequence of this MR mutation," Lifton explained, "is that the kidney reabsorbs more salt and water than it otherwise would, and as a result blood pressure goes up."

To determine if mutations in MR could cause increased renal salt reabsorption, and hypertension, the co-authors screened blood samples from 75 patients with early-onset, severe hypertension. One 15-year-old boy with the disorder had a missense genomic mutation, substituting a leucine amino acid for serine.

Of this youngster's 23 relatives tested, the Science paper reported, "11 had been diagnosed with severe hypertension before age 20. All carried the mutant MR." It added: "Three deceased pedigree members with early-onset hypertension all died of heart failure before age 50."

On this cardiac score, Lifton pointed out, "Hypertension is certainly one of the major risk factors for heart attack, heart failure and stroke. The proximate cause in myocardial infarction and stroke is that the high blood pressure damages the blood vessel wall, leading to injury-repair mechanisms that ultimately cause either thrombosis - the clotting of the vessel - or in the case of stroke, to possible vessel rupture, leading to hemorrhage.

"If you look at people who develop atherosclerosis, heart disease and stroke," Lifton went on, "the major risk factors are smoking, diabetes, cholesterol and hypertension."

At Atomic Level, A Tale Of Two Helices

After characterizing this familial pregnancy-induced hypertension and figuring out its molecular cause, Lifton and his co-authors went on to determine the mechanism by which the mutation acts at the atomic level. "We looked at the structure of the wild type and the mutant receptor," he recounted, "and determined how the mutation allows progesterone to activate the receptor. And the solution to that turned out to be unexpectedly interesting, because it identified an interaction between two alpha-helices of the receptor protein, which is essential in its activation by progesterone.

"The almost identical interactions are present in every other steroid hormone receptor," he pointed out. "And up to now their significance for receptor activation was not anticipated. As a consequence, we now know that that interaction is key, and one can imagine developing new steroid receptor antagonists that act by interrupting that interaction between these two helices."

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