NR3C2@yaoxinzhi:600983 JSONTXT

screened the mineralocorticoid receptor in 75 patients with early onset of severe hypertension (605115). In a 15-year-old boy with severe hypertension, a C-to-T substitution, changing codon 810 of the hormone-binding domain from a serine to a leucine, was identified. The ser810-to-leu (S810L) mutation was identified in heterozygous state in 11 family members of this proband who had been diagnosed with severe hypertension before the age of 20 years, resulting in constitutive MR activity and altered receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists. This resulted in profound exacerbation of hypertension during 5 pregnancies in 2 affected women in this kindred. Structural and biochemical studies indicated that S810L 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 wildtype receptor. This helix 5-helix 3 interaction is highly conserved among diverse nuclear hormone receptors, suggesting its general role in receptor activation. The effect of the S810L mutation was to invert the mineralocorticoid receptor from aldosterone-responsive to progesterone-responsive, with development of hypertension during pregnancy. This was the first mendelian form of preeclampsia to be identified. Ordinarily, blood pressure goes down during early stages of pregnancy. 

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