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- Title
Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy.
- Authors
Geller, D S; Farhi, A; Pinkerton, N; Fradley, M; Moritz, M; Spitzer, A; Meinke, G; Tsai, F T; Sigler, P B; Lifton, R P
- Abstract
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.
- Publication
Science (New York, N.Y.), 2000, Vol 289, Issue 5476, p119
- ISSN
0036-8075
- Publication type
Journal Article
- DOI
10.1126/science.289.5476.119