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Gene mutation linked to hypertension during pregnancy
By Julie Buckles

The mutated gene of a 15-year-old boy has shed light on a condition perplexing to researchers: pregnancy-induced hypertension. It is especially puzzling since pregnancy typically lowers—not raises—blood pressure, yet six percent of childbearing women in the United States suffer the debilitating and sometimes fatal condition.

looking for a mutation in the mineralocorticoid receptor

Researchers at the Yale School of Medicine recently uncovered a mutation in the mineralocorticoid steroid hormone receptor that causes rare cases of childhood high blood pressure and is exacerbated by progesterone—a steroid hormone that dramatically increases during pregnancy. Equally important to discovering the mutation, says nephrologist David Geller, is understanding how a steroid hormone—in this case progesterone—works with steroid hormone receptors.

The mineralocorticoid receptor, located in the kidney cells, regulates blood pressure by instructing the kidney to take in more or less salt and water, resulting in higher or lower blood pressure. It works a bit like a garden hose with a nozzle at the end, says Geller, who discovered the mutated receptor. "If you turn on the spigot, more water enters the hose, the hose fills up and the pressure increases. If you turn down the flow, the hose empties and the pressure is lower."

Researchers, who reported their findings in a recent issue of Science, suspected a mutation in the mineralocorticoid receptor might influence the way blood pressure builds, much like a spigot stuck in the "on" position too long. They screened 75 children with severe hypertension, looking for a mutation in the mineralocorticoid receptor. The odds were good that if it existed, they would find it in one of these children. "It's such an abnormal picture to have high blood pressure at a young age that it's more likely to be genetically related," Geller says, "At an older age, high blood pressure is a more common disease caused by external factors like exercise, alcohol consumption and salt-intake."

a unique opportunity to pinpoint the cause of this particular case of hypertension

They hit the jackpot with one 15-year-old boy. "As soon as we started looking at the mutation it seemed likely it was going to be interesting," Geller says. And how. It turned out the boy has a large family. Geller and his colleagues at Howard Hughes Medical Institute at Yale evaluated the boy's 23 relatives. Of those, 11 had been diagnosed with severe hypertension before age 20—an astounding percentage considering it occurs in only one percent of the population. All 11 have the mutation in the mineralocorticoid receptor. A normal receptor opens or closes salt channels to stabilize blood pressure, "but in this family the receptor is always turned on," Geller says.

Even more intriguing is that the steroid hormone aldosterone, which normally triggers the receptor, is absent. So, if aldosterone isn't activating the receptor, what is? To find out, researchers tested the activity of the receptor in a test tube. The mutation lies in the part of the receptor that recognizes and binds to the hormone, "so we suspected it would respond to a different hormone," Geller says.

Geller and his associates discovered that progesterone—which typically lowers blood pressure—had the opposite affect on the mutated receptor. Since progesterone increases a dramatic 100-fold during pregnancy, it offered researchers a unique opportunity to pinpoint the cause of this particular case of hypertension.

findings will provide insight into more common forms of high blood pressure

They examined the clinical histories of the two women in the family who had given birth. Not surprising, both women had suffered severe hypertension during pregnancy, a serious condition that causes intrauterine growth retardation, early deliveries and pre-eclampsia, a potentially fatal condition. The two women produced five healthy babies between them but with complications. They delivered pre-term babies via Caesarian section and both women were advised not to have any more children.

Researchers say it is too early to discuss remedies for pregnancy-induced hypertension. "In general, we still don't have a good idea why women become hypertensive during pregnancy, but here's one example where we knew exactly why," Geller says. As for the men and non-pregnant women in the family, researchers aren't sure what triggers the mutated receptor since progesterone levels are normally low in men and stable in non-pregnant women. Geller says they have reason to suspect that the receptors are always turned on or that other types of progesterone switch the receptors on, "but it's harder to prove."

The Yale team is already developing a genetically altered mouse with a mutation in the mineralocorticoid receptor gene, a complicated process that could take more than a year. Ultimately, researchers hope their findings about steroid receptors will provide insight into more common forms of high blood pressure as well as diabetes, thyroid disease, and prostrate and breast cancer. "What's really exciting here is that we are learning how steroid receptors work and that they control a lot of processes of life," Geller says.

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Geller, D.S. et al. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science 289, 119-123 (July 7, 2000).

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