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Science 7 July 2000:
Vol. 289. no. 5476, pp. 119 - 123
DOI: 10.1126/science.289.5476.119
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Reports

Activating Mineralocorticoid Receptor Mutation in Hypertension Exacerbated by Pregnancy

David S. Geller, 12 Anita Farhi, 12 Nikki Pinkerton, 12 Michael Fradley, 12 Michael Moritz, 4 Adrian Spitzer, 4 Gretchen Meinke, 13 Francis T. F. Tsai, 13 Paul B. Sigler, 13* Richard P. Lifton 123dagger

Hypertension and pregnancy-related hypertension are major public health problems of largely unknown causes. We describe a mutation in the mineralocorticoid receptor (MR), S810L, that causes early-onset hypertension that is markedly exacerbated in pregnancy. This mutation results in constitutive MR activity and alters receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists. Structural and biochemical studies indicate that the mutation results in the gain of a van der Waals interaction between helix 5 and helix 3 that substitutes for interaction of the steroid 21-hydroxyl group with helix 3 in the wild-type receptor. This helix 5-helix 3 interaction is highly conserved among diverse nuclear hormone receptors, suggesting its general role in receptor activation.

1 Howard Hughes Medical Institute,
2 Departments of Genetics, Internal Medicine (Nephrology) and
3 Molecular Biophysics and Biochemistry, Yale University School of Medicine, Boyer Center for Molecular Medicine, Room 154, 295 Congress Avenue, New Haven, CT 06510, USA.
4 Department of Pediatrics, Albert Einstein College of Medicine, New York, NY 10461, USA.
*   Deceased.

dagger    To whom correspondence should be addressed. E-mail: richard.lifton{at}yale.edu

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