One in five Americans and Europeans has high blood pressure, a dangerous disorder whose numerous genetic causes are only beginning to be revealed. Now a team of researchers has uncovered an important piece of the puzzle: a gene mutation that leads to early-onset hypertension. The mutation may help explain the causes of more common forms of high blood pressure and may also explain why some women's blood pressure rises sharply during pregnancy.
The team, led by geneticist Richard Lifton of Yale Medical School, had previously linked a suite of genes to blood pressure abnormalities. To find new mutations in those genes that cause high blood pressure, they systematically screened patients with hypertension. Among them was a 15-year-old boy with severe hypertension. The researchers discovered he had a mutation in the mineralocorticoid receptor, a protein in kidney cells that is involved in the body's handling of salt. When activated by the steroid hormone aldosterone, this receptor normally triggers a cascade of molecular events that cause kidney cells to absorb salt and water for release back into the blood. This can help prevent dehydration on a hot summer day, but it also raises blood pressure.
Lifton and his colleagues then found that the mutation caused hypertension before age 20 in all the boy's relatives who had inherited it. They found the reason by engineering cultured cells to glow when their mineralocorticoid receptor was activated. Cells engineered with the mutant receptor glowed all the time--even in the absence of aldosterone. The mutant receptor appeared to be permanently stuck in the "on" position, Lifton and colleagues report in the 7 July issue of Science.
To their surprise, they also found that progesterone, which gums up the normal receptor, strongly stimulated the mutant version. Because progesterone levels increase dramatically during pregnancy, Lifton wondered whether the hormone would exacerbate blood pressure problems in pregnant women who have this mutation. It seemed to: Worsening hypertension had plagued all five of the pregnancies of two women carrying the mutated receptor. Lifton does not think this particular mutation will turn out to be common. But he says the findings suggest that the salt recycling pathway, in which the mutant receptor acts, could be important in hypertension. They also suggest that hormones like progesterone might in some cases overstimulate the pathway.
"It's a genuine tour de force," says nephrologist Friedrich Luft of the Max Delbrück Center for Molecular Medicine in Berlin, Germany. "It uncovers new and unexpected mechanisms for hypertension" in humans, he says, that could one day lead to better treatments and new diagnostic tools for the disorder.