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 types
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Comment
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adolescent
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Aldosterone / metabolism*
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Amino Acid Sequence
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Amino Acid Substitution
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Base Sequence
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Binding, Competitive
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Dimerization
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Female
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Heterozygote
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Humans
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Hypertension / etiology
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Hypertension / genetics*
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Hypertension / metabolism
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Male
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Models, Molecular
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Molecular Sequence Data
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Pedigree
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Point Mutation
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Pregnancy
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Pregnancy Complications, Cardiovascular* / etiology
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Pregnancy Complications, Cardiovascular* / metabolism
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Progesterone / metabolism*
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Protein Conformation
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Protein Structure, Secondary
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Receptors, Mineralocorticoid / chemistry
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Receptors, Mineralocorticoid / genetics*
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Receptors, Mineralocorticoid / metabolism*
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Receptors, Steroid / chemistry
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Receptors, Steroid / metabolism
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Steroids / metabolism
Substances
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Receptors, Mineralocorticoid
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Receptors, Steroid
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Steroids
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Aldosterone
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Progesterone