Activating Mineralocorticoid Receptor Mutation in Hypertension Exacerbated by Pregnancy
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:
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Science
- Pub Date:
- July 2000
- DOI:
- 10.1126/science.289.5476.119
- Bibcode:
- 2000Sci...289..119G
- Keywords:
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- MEDICINE