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.
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Rare point mutations altering the structure of the ligand-binding domain of the mineralocorticoid receptor may result in mild constitutive activation as well as permitting binding and activation of the receptor by progesterone, resulting in severe hypertension that begins in adolescence and worsens with pregnancy.
“Rare point mutations altering the structure of the ligand-binding domain of the mineralocorticoid receptor may result in mild constitutive activation as well as permitting binding and activation of the receptor by progesterone, resulting in severe hypertension that begins in adolescence and worsens with pregnancy (644).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [644]
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- Authors
- Geller, D. S., Farhi, A., Pinkerton, N., Fradley, M., Moritz, M., Spitzer, A., Meinke, G., Tsai, F. T. F., Sigler, P. B., & Lifton, R. P.
- Affiliations
- Howard Hughes Medical Institute (US)
- Albert Einstein College of Medicine (US)
- Corresponding author
- Sigler, Paul B.
- Lifton, Richard P.
- ORCID
- Venue
- Science
- Published
- 2000-07-07
- Volume
- 289
- Issue
- 5476
- Pages
- 119-123
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2052724934
- Cited by
- 675
- References
- 13
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 19 · 2023: 33 · 2022: 19 · 2021: 15 · 2020: 14 · 2019: 20 · 2018: 23 · 2017: 23 · 2016: 18 · 2015: 20 · 2014: 22 · 2013: 17 · 2012: 39
- FWCI
- 27.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- mineralocorticoid receptor, early-onset hypertension, gestational hypertension, constitutive receptor activation, van der Waals interactions
- MeSH terms
- Adolescent, Aldosterone, Amino Acid Sequence, Base Sequence, Binding, Competitive, Female, Heterozygote, Humans, Hypertension, Male, Models, Molecular, Molecular Sequence Data, Pedigree, Pregnancy, Pregnancy Complications, Cardiovascular, Progesterone, Protein Conformation, Receptors, Steroid, Steroids, Point Mutation, Protein Structure, Secondary, Receptors, Mineralocorticoid, Dimerization, Amino Acid Substitution
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