30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor mutations

Abstract

Aldosterone and the mineralocorticoid receptor (MR) are key elements for maintaining fluid and electrolyte homeostasis as well as regulation of blood pressure. Loss-of-function mutations of the MR are responsible for renal pseudohypoaldosteronism type 1 (PHA1), a rare disease of mineralocorticoid resistance presenting in the newborn with weight loss, failure to thrive, vomiting and dehydration, associated with hyperkalemia and metabolic acidosis, despite extremely elevated levels of plasma renin and aldosterone. In contrast, a MR gain-of-function mutation has been associated with a familial form of inherited mineralocorticoid hypertension exacerbated by pregnancy. In addition to rare variants, frequent functional single nucleotide polymorphisms of the 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 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 on stress and cognitive functions in the general population.

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

“…In vertebrates, the steroid NRs include estrogen receptor (ER) isoforms ERα (NR3A1) and ERβ (NR3A2) together with the androgen receptor (AR/NR3C4), the glucocorticoid receptor (GR/NR3C1), the mineralocorticoid receptor (MR/NR3C2) and the progesterone receptor (PR/NR3C3). Phylogenetic studies show that AR, GR, MR and PR comprise a subfamily of so-called oxosteroid NRs, which markedly differ from both ER isoforms (Bledsoe et al 2002, Evans & Mangelsdorf 2014, Gallastegui et al 2015, Zennaro & Fernandes-Rosa 2017, Katzenellenbogen et al 2018. This phylogenetic separation is also reflected at the level of tertiary and quaternary structures, as we will discuss below.…”

“…For instance, the ER is a key driver of 70% of breast cancer subtypes that require estrogen hormones for progression, and different point mutations in the ER genes are linked to acquired resistance to commonly used estrogenblocking drugs such as tamoxifen (Kojetin et al 2008, Katzenellenbogen et al 2018, Nasrazadani et al 2018, Reinert et al 2018. Regarding oxosteroid receptors, single-residue mutations in GR and MR genes have mainly been associated to loss-of-function phenotypes (Zennaro & Fernandes-Rosa 2017). However, the most conspicuous association between a nuclear receptor and human disease links the AR to several biomedical conditions, as we briefly discuss below.…”

“…Further, loss-of-function mutations in the NR3C2/MR gene are responsible for renal pseudohypoaldosteronism type 1 (MIM #177735), a rare disease of mineralocorticoid resistance characterized by sodium and potassium imbalances that manifests at birth with weight loss and dehydration despite elevated plasma levels of aldosterone. Conversely, an activating MR mutation that reshapes its LBP (p.S810L) has been associated with a severe form of inherited hypertension (Kino & Chrousos 2001, Zennaro & Fernandes-Rosa 2017. Finally, PR mutations are less frequent but they have been associated to an increased risk of breast, endometrial and colon cancer (Agoulnik et al 2004).…”

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The scientific impact of cloning the mineralocorticoid receptor: 30 years on

“…We cannot freely and blindly generalize from mouse to man -or even from mouse to rat: one has a gall bladder, for instance, and the other does not. This is where the contribution from Paris, by Maria-Christina Zennaro and Fabio FernandesRosa, comes in (Zennaro & Fernandes-Rosa 2017).…”

Investigating the Role of Mineralocorticoid Receptor Signaling in Cancer Biology in the Genomic Era

“…Overall, the observed rate of somatic mutations of MR has been shown to be significantly lower with respect to the expected rate suggesting MR does not tolerate well mutations with functional constraints [81]. On the other hand, functional mutations of MR have been identified in different contexts including renal pseudohypoaldosteronism as well as hypertension [81,82]. In addition, relatively different residues in the DNA-binding domain of MR seem to be affected between type I pseudohypoaldosteronism and cancers [83].…”