Activating mineralocorticoid receptor mutation in hypertension exacerbatedby pregnancy

Hypertension and pregnancy-related hypertension are major public health pro blems of largely unknown causes. We describe a mutation in the mineralocort icoid receptor (MR), S810L, that causes early-onset hypertension that is ma rkedly exacerbated in pregnancy. This mutation results in constitutive MR a ctivity and alters receptor specificity, with progesterone and other steroi ds lacking 21-hydroxyl groups, normally MR antagonists, becoming potent ago nists. Structural and biochemical studies indicate that the mutation result s in the gain of a van der Waals interaction between helix 5 and helix 3 th at 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 con served among diverse nuclear hormone receptors, suggesting its general role in receptor activation.