Activating Mineralocorticoid Receptor Mutation in Hypertension Exacerbated by Pregnancy
David S. Geller,
12
Anita Farhi,
12
Nikki Pinkerton,
12
Michael Fradley,
12
Michael Moritz,
4
Adrian Spitzer,
4
Gretchen Meinke,
13
Francis T. F. Tsai,
13
Paul B. Sigler,
13*
Richard P. Lifton
123
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.
1 Howard Hughes Medical Institute,
2 Departments of Genetics, Internal Medicine
(Nephrology) and
3 Molecular Biophysics and
Biochemistry, Yale University School of Medicine, Boyer Center for
Molecular Medicine, Room 154, 295 Congress Avenue, New Haven, CT 06510, USA.
4 Department of Pediatrics, Albert Einstein
College of Medicine, New York, NY 10461, USA.
*
Deceased.
To whom correspondence should be addressed. E-mail:
richard.lifton{at}yale.edu
