Activating Mineralocorticoid Receptor Mutation in Hypertension Exacerbated by Pregnancy

• Published in: Science (American Association for the Advancement of Science) 2000-07, Vol.289 (5476), p.119-123
• Main Authors: Geller, David S., Farhi, Anita, Pinkerton, Nikki, Fradley, Michael, Moritz, Michael, Spitzer, Adrian, Meinke, Gretchen, Francis T. F. Tsai, Sigler, Paul B., Lifton, Richard P.
• Format: Article
• Language: English
• Subjects: Adolescent; Aldosterone - metabolism; Amino Acid Sequence; Amino Acid Substitution; Amino acids; Base Sequence; Binding, Competitive; Biological and medical sciences; Blood pressure; Causes of; COS cells; Dimerization; Diseases of mother, fetus and pregnancy; Female; Genetic mutation; Gestational hypertension; Gynecology. Andrology. Obstetrics; Heterozygote; Humans; Hypertension; Hypertension - etiology; Hypertension - genetics; Hypertension - metabolism; Hypertension in pregnancy; Male; Medical research; Medical sciences; mineralcorticoid receptors; Models, Molecular; Molecular Sequence Data; Mutation; nuclear homrmone receptors; Nuclear receptors; Pedigree; Plasmids; Point Mutation; Preeclampsia; Pregnancy; Pregnancy Complications, Cardiovascular - etiology; Pregnancy Complications, Cardiovascular - metabolism; Pregnancy. Fetus. Placenta; Progesterone - metabolism; Protein Conformation; Protein Structure, Secondary; Receptors; Receptors, Mineralocorticoid - chemistry; Receptors, Mineralocorticoid - genetics; Receptors, Mineralocorticoid - metabolism; Receptors, Steroid - chemistry; Receptors, Steroid - metabolism; Steroids; Steroids - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.289.5476.119

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.