Human Mineralocorticoid Receptor Genomic Structure and Identification of Expressed Isoforms

Zennaro, Maria‐Christina; Keightley, Maria-Cristina; Kotelevtsev, Yuri; Conway, Gerard S.; Soubrier, Florent; Fuller, Peter J.

doi:10.1074/jbc.270.36.21016

Cited by 136 publications

(65 citation statements)

References 44 publications

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“…They are alternatively spliced to two 6 kb long mRNA isoforms that differ in their 5 0 -untranslated region and are expressed in a tissue specific manner (1). Both mRNA subtypes result in the same 107 kDa receptor protein (2)(3)(4). In addition, different splice site usage (donor splice site: end of exon 3 or intron c) of the MR-mRNA has been observed in various rat tissues and human white blood cells.…”

Section: Introductionmentioning

confidence: 99%

Mineralocorticoid receptor splice variants in different human tissues

Wickert

Watzka

Bolkenius

et al. 1998

European Journal of Endocrinology

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The mineralocorticoid receptor (MR), a member of the steroid receptor family, acts as a transcription factor and mediates both aldosterone and cortisol effects. Aldosterone specificity in some tissues results from the inactivation of competing cortisol into cortisone by 11b-hydroxysteroid dehydrogenase. In other tissues MR and the glucocorticoid receptor show overlapping physiological effects or may act together by forming a heterodimer. An additional MR splice variant (MR+4) has been found in different mRNA samples from rat tissues and human white blood cells, thereby implying additional modes of MR-regulated effects. We therefore looked for the presence of these two MR-mRNA isoforms in human classical aldosterone target tissues and various other tissues. MR-mRNA was found in all samples investigated, thereby showing the expression of MR to be more abundant than has been observed thus far. In addition, the MR+4-mRNA variant was also found in all the tissues examined. European Journal of Endocrinology 138 702-704

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Section: Introductionmentioning

confidence: 99%

Mineralocorticoid receptor splice variants in different human tissues

Wickert

Watzka

Bolkenius

et al. 1998

European Journal of Endocrinology

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“…We have shown previously that the human MR (hMR) gene is composed of ten exons (21) including the two first untranslated exons 1␣ and 1␤. The P1 and P2 regions upstream of exons 1␣ and 1␤, respectively, have been characterized as functional alternative promoters (22).…”

mentioning

confidence: 99%

Alteration of Cardiac and Renal Functions in Transgenic Mice Overexpressing Human Mineralocorticoid Receptor

Menuet¹,

Isnard²,

Bichara³

et al. 2001

Journal of Biological Chemistry

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110

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The mineralocorticoid receptor (MR), a ligand-dependent transcription factor, mediates aldosterone actions in a large variety of tissues. To explore the functional implication of MR in pathophysiology, transgenic mouse models were generated using the proximal human MR (hMR) promoter to drive expression of hMR in aldosterone target tissues. Tissue-specific analysis of transgene expression in two independent transgenic animal (TG) lines by ribonuclease protection assays revealed that hMR is expressed in all mineralocorticoid-sensitive tissues, most notably in the kidney and the heart. TG exhibit both renal and cardiac abnormalities. Enlarged kidneys were histologically associated with renal tubular dilation and cellular vacuolization whose prevalence increased with aging. Renal clearance studies also disclosed a significant decrease in urinary potassium excretion rate in TG. hMRexpressing animals had normal blood pressure but developed mild dilated cardiomyopathy (increased left ventricle diameters and decreased shortening fraction), which was accompanied by a significant increase in heart rate. Differential gene expression analysis revealed a 2-to 5-fold increase in cardiac expression of atrial natriuretic peptide, serum-and glucocorticoid-induced kinase, and early growth response gene 1 as detected by microarrays; renal serum-and glucocorticoid-induced kinase was also induced significantly. Altogether, TG exhibited specific alteration of renal and cardiac functions, thus providing useful pathophysiological models to gain new insights into the tissue-specific mineralocorticoid signaling pathways.

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“…The main difference between this and previous studies was the technical approach for detecting mutations. Indeed, after the cloning of the NR3C2 gene (Zennaro et al 1995), genomic sequencing became available allowing to detect mutations directly on DNA. A p.Arg590X MR nonsense mutation was subsequently detected in affected patients from the kindred studied by Zennaro and coworkers, which was not present on MR mRNA in peripheral blood lymphocytes from the same patient (Geller et al 2006).…”

Section: Mr Mutations In Pha1mentioning

confidence: 99%

“…The human MR is a protein of 984 amino acids with a modular structure comprising three separate domains with specific functions (Viengchareun et al 2007, Yang & Young 2009). The NR3C2 gene is composed of 8 coding exons (Zennaro et al 1995); exon 2 codes for the N-terminal domain (NTD), involved in transcriptional activation and intramolecular interactions, whereas exons 3 and 4 code for the DNA-binding domain (DBD). This central domain of the protein folds into two zincfinger structures that are involved in DNA recognition and receptor dimerization (Hudson et al 2014).…”

Section: Mr Mutations In Pha1mentioning

confidence: 99%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor mutations

Zennaro

Fernandes-Rosa

2017

Journal of Endocrinology

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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.

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Human Mineralocorticoid Receptor Genomic Structure and Identification of Expressed Isoforms

Cited by 136 publications

References 44 publications

Mineralocorticoid receptor splice variants in different human tissues

Mineralocorticoid receptor splice variants in different human tissues

Alteration of Cardiac and Renal Functions in Transgenic Mice Overexpressing Human Mineralocorticoid Receptor

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor mutations

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