Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy |
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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 |
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Institution: | Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, Boyer Center for Molecular Medicine, Room 154, 295 Congress Avenue, New Haven, CT 06510, USA. |
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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. |
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