title: 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.
authors.affiliation: 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.
authors.forename: D S
authors.initials: DS
authors.lastname: Geller
authors.forename: A
authors.initials: A
authors.lastname: Farhi
authors.forename: N
authors.initials: N
authors.lastname: Pinkerton
authors.forename: M
authors.initials: M
authors.lastname: Fradley
authors.forename: M
authors.initials: M
authors.lastname: Moritz
authors.forename: A
authors.initials: A
authors.lastname: Spitzer
authors.forename: G
authors.initials: G
authors.lastname: Meinke
authors.forename: F T
authors.initials: FT
authors.lastname: Tsai
authors.forename: P B
authors.initials: PB
authors.lastname: Sigler
authors.forename: R P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000293:Adolescent; D000450:Aldosterone / Q000378:metabolism*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D001667:Binding, Competitive; D019281:Dimerization; D005260:Female; D006579:Heterozygote; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000209:etiology / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D018161:Receptors, Mineralocorticoid / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011987:Receptors, Steroid / Q000737:chemistry / Q000378:metabolism; D013256:Steroids / Q000378:metabolism
chemical_list: D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid; D013256:Steroids; D000450:Aldosterone; D011374:Progesterone