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," said molecular geneticist Richard Lifton, of the Howard Hughes Medical Institute at Yale University (New Haven, Connecticut), "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 added, "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 said, "pregnancy-induced hypertension affects 6% of all pregnancies, an incidence believed to be fairly consistent worldwide. So that would be about 8 million pregnancies a year." The disorder "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."

Lifton added: "Even in the non-pregnant state, 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 on the receptor mutation in the July 7, 2000, issue of Science. "This represents a first link between a normal pregnancy change in physiology that when it goes wrong causes this severe form of the pregnancy disorder," he said. "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." To explain this link, Lifton resorted to an 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. That's in essence what happens with this disease."

Lifton noted, "Our bodies have a set point for salt balance. 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." He said 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."

What happens as a consequence of this MR mutation, Lifton said, "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. Three deceased pedigree members with early-onset hypertension all died of heart failure before age 50."

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

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