234 1 M-C ZENNARO and MR mutations 234:1 T93–T106 Thematic Review F FERNANDES-ROSA 30 YEARS OF THE MINERALOCORTICOID RECEPTOR Mineralocorticoid receptor mutations Maria-Christina Zennaro1,2,3 and Fabio Fernandes-Rosa1,2,3 Correspondence 1INSERM, Paris Cardiovascular Research Center, Paris, France should be addressed 2Université Paris Descartes, Sorbonne Paris Cité, Paris, France to M-C Zennaro 3Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Email Paris, France maria-christina.zennaro@ inserm.fr Abstract Aldosterone and the mineralocorticoid receptor (MR) are key elements for maintaining Key Words fluid and electrolyte homeostasis as well as regulation of blood pressure. Loss-of- f mineralocorticoid function mutations of the MR are responsible for renal pseudohypoaldosteronism type receptor 1 (PHA1), a rare disease of mineralocorticoid resistance presenting in the newborn with f pseudohypoaldosteronism type 1- PHA1 weight loss, failure to thrive, vomiting and dehydration, associated with hyperkalemia f aldosterone and metabolic acidosis, despite extremely elevated levels of plasma renin and f hormone receptors aldosterone. In contrast, a MR gain-of-function mutation has been associated with a f nuclear receptor familial form of inherited mineralocorticoid hypertension exacerbated by pregnancy. In Endocrinology addition to rare variants, frequent functional single nucleotide polymorphisms of the of MR are associated with salt sensitivity, blood pressure, stress response and depression in the general population. This review will summarize our knowledge on MR mutations in Journal PHA1, reporting our experience on the genetic diagnosis in a large number of patients performed in the last 10 years at a national reference center for the disease. We will also discuss the influence of rare MR variants on blood pressure and salt sensitivity as well as Journal of Endocrinology on stress and cognitive functions in the general population. (2017) 234, T93–T106 Introduction Aldosterone and the mineralocorticoid receptor (MR) transcription factor by binding to specific hormone- play a key role in the regulation of electrolyte balance responsive elements located in regulatory regions of and blood pressure. Abnormalities in aldosterone and target genes. In the distal nephron, the MR induces an MR function lead to salt-losing disorders or hypertension. aldosterone-dependent dynamic transcriptional program, Aldosterone is synthesized in the zona glomerulosa of leading to rapid induction of different signaling pathways the adrenal cortex under the control of different stimuli, and transcriptional cascades modulating the activity mainly the renin-angiotensin system and potassium. of major structural components of ion transport. In Aldosterone regulates transepithelial ionic transport by the aldosterone-sensitive distal nephron, aldosterone stimulating sodium reabsorption and potassium secretion regulates sodium and potassium balance by stimulating in the distal tubule of the kidney, the colon, salivary and the activity of the epithelial sodium channel ENaC and sweat glands via binding to the MR (Pearce et al. 2003). the Na+-K+-ATPase (Stockand 2002). The MR rapidly The MR is a member of the steroid hormone receptor induces transcription of the serum- and glucocorticoid- subgroup of the nuclear receptor superfamily (Nuclear regulated kinase (sgk) 1, which directly stimulates ENaC Receptor Committee 1999) and acts as a ligand-dependent activity by phosphorylating Nedd4-2, thus reducing http://joe.endocrinology-journals.org © 2017 Society for Endocrinology This paper is part of a thematic review section on 30 Years of the Mineralocorticoid DOI: 10.1530/JOE-17-0089 Published by Bioscientifica Ltd. Receptor. The guest editors for this section were John Funder and Printed in Great Britain Maria Christina Zennaro. Downloaded from Bioscientifica.com at 09/30/2021 05:30:34PM via free access 10.1530/JOE-17-0089 Thematic Review M-C ZENNARO and MR mutations 234:1 T94 F FERNANDES-ROSA ubiquitylation, retrieval and degradation of ENaC from occupation by glucocorticoids (Edwards et al. 1988, (Bhalla et al. 2006). In parallel, transcriptional regulation Funder et al. 1988 for a detailed review, see the article by of the deubiquitylating enzyme Usp2-45 increases ENaC Funder in this issue). In addition to local metabolism of surface expression and activity (Verrey et al. 2008). MR the glucocorticoid hormones, intrinsic properties of the also increases the expression of glucocorticoid-induced MR, in terms of ligand discrimination and coregulator leucine zipper protein (GILZ), which acts in parallel recruitment, contribute to modulate receptor selectivity with sgk1 to increase ENaC localization at the plasma and transcriptional effects (Farman & Rafestin-Oblin membrane (Soundararajan et al. 2005). 2001). In unprotected tissues, like adipose tissue and the In addition to its effects on the kidney, a large brain, MR is a high-affinity receptor for glucocorticoids; number of studies have highlighted the role of the MR however, depending on the cell type and environmental in regulating the physiological processes in non-epithelial conditions, glucocorticoids may have agonist or tissues, including the heart, vessels, adipose tissue and the antagonist effects (Funder 2005). brain (Jaisser & Farman 2016). The study of MR variants has contributed It is important to remember that MR possesses the enormously to our understanding of structure–function same affinity for aldosterone and for the physiological relationships in the MR. Frequent genetic variants glucocorticoid cortisol (corticosterone in rats and of the MR are associated with salt sensitivity, blood mice), which has plasma concentrations 100- to 1000- pressure, stress response and depression. In extreme fold higher than those of aldosterone. In aldosterone cases, loss-of-function mutations are responsible for renal target tissues, the enzyme 11-beta-hydroxysteroid pseudohypoaldosteronism type 1 (PHA1), whereas a gain- dehydrogenase type 2 (11HSD2) converts cortisol (and of-function mutation has been associated with a familial corticosterone) into the inactive metabolites cortisone and form of inherited mineralocorticoid hypertension. More 11-dehydrocorticosterone, thus modulating intracellular than 380 rare coding variants have been described in the glucocorticoid levels and protecting the nonselective MR major transcript of the NR3C2 gene, coding for the MR, Endocrinology of Journal Figure 1 Three-dimensional homology model of the MR LBD. (A) Overall structure of the MR LBD, α-helices are drawn as ribbons and β-strands as arrows. Aldosterone is inserted into the ligand-binding pocket (carbon atoms are in white and oxygen atoms in red). (B) Linear scheme indicating amino acids of the MR LBD-contacting aldosterone. Hydrogen bonds are depicted as arrows, van der Waals contacts as dashed lines. W, water molecule. Reprinted from Molecular and Cellular Endocrinology, Volume 350, Huyet J, Pinon GM, Fay MR, Rafestin-Oblin ME & Fagart J, Structural determinants of ligand binding to the mineralocorticoid receptor, pages 187–195. Copyright 2012, with permission from Elsevier. http://joe.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-17-0089 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 05:30:34PM via free access Thematic Review M-C ZENNARO and MR mutations 234:1 T95 F FERNANDES-ROSA in the Exome Aggregation Consortium (ExAC) (Lek et al. numbers MIM#177735 and ORPHA#71871) is a mild form 2016), which aggregates exome sequencing data from of primary mineralocorticoid resistance and represents a wide variety of sequencing projects, with constraint the most frequent form of the disease. It is due to loss-of- metrics indicating that NR3C2 is intolerant for both function mutations in the NR3C2 gene (Geller et al. 1998, missense and nonsense mutations. This suggests that rare Sartorato et al. 2003, Pujo et al. 2007). The prevalence, variants (MAF less than 0.5%) and also common single- as estimated from recruitment through a national nucleotide polymorphism, with a minor allele frequency reference center for rare diseases (MC. Zennaro, genetics (MAF) in the population ≥5%, may have functional laboratory, HEGP, see below) is ~1 per 80,000 newborns, consequences on mineralocorticoid homeostasis in the but may be underestimated due to phenotypic variability, general population and modulate disease susceptibility including asymptomatic cases. Patients show various whenever they significantly affect protein function or degrees of failure to thrive, dehydration and vomiting, amount. with hyponatremia, hyperkalemia and inappropriately high urinary sodium excretion. In contrast, urinary potassium excretion is low, with reduced fractional Pseudohypoaldosteronism type 1 potassium excretion and transtubular potassium gradient (Rodriguez-Soriano et al. 1990). Diagnosis is confirmed by The integrity of the mineralocorticoid axis is particularly elevated plasma renin and aldosterone levels. Symptoms relevant in the neonatal period, where renal regulation of renal PHA1 improve in childhood and, generally, salt of water and electrolyte balance is impaired due to supplementation, which is required to correct the sodium immature tubular function (Holtback & Aperia 2003). losses, can be discontinued around age 18–24 months. Events such as prematurity or infections may lead to salt Older children are generally