G-protein-coupled receptors in aldosterone-producing adenomas: a potential cause of hyperaldosteronism

Ye, Ping; Mariniello, Barbara; Mantero, Franco; Shibata, Hirotaka; Rainey, William E.

doi:10.1677/joe-07-0037

Cited by 106 publications

(110 citation statements)

References 69 publications

(69 reference statements)

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“…This RNA was again reversetranscribed to cDNA and amplified as described above. For qPCR, 1 ng prepared cDNA was mixed with Fast Universal PCR Master Mix (Applied Biosystems) and TaqMan primer/probe mix specific for CYP11B2 as previously reported (39). TaqMan primer/probe mix for peptidylprolyl isomerase A (cyclophilin A) transcript was purchased from Applied Biosystems and used for normalization.…”

Section: Methodsmentioning

confidence: 99%

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

Nishimoto

Tomlins

Kuick

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

269

273

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Primary aldosteronism (PA) represents the most common cause of secondary hypertension, but little is known regarding its adrenal cellular origins. Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue. PA-causing aldosteroneproducing adenomas (APAs) harbor mutations in genes encoding ion channels/pumps that alter intracellular calcium homeostasis and cause renin-independent aldosterone production through increased CYP11B2 expression. Herein, we hypothesized that APCCs have APArelated aldosterone-stimulating somatic gene mutations. APCCs were studied in 42 normal adrenals from kidney donors. To clarify APCC molecular characteristics, we used microarrays to compare the APCC transcriptome with conventional adrenocortical zones [zona glomerulosa (ZG), zona fasciculata, and zona reticularis]. The APCC transcriptome was most similar to ZG but with an enhanced capacity to produce aldosterone. To determine if APCCs harbored APA-related mutations, we performed targeted next generation sequencing of DNA from 23 APCCs and adjacent normal adrenal tissue isolated from both formalin-fixed, paraffin-embedded, and frozen tissues. Known aldosterone driver mutations were identified in 8 of 23 (35%) APCCs, including mutations in calcium channel, voltage-dependent, L-type, α1D-subunit (CACNA1D; 6 of 23 APCCs) and ATPase, Na + /K + transporting, α1-polypeptide (ATP1A1; 2 of 23 APCCs), which were not observed in the adjacent normal adrenal tissue. Overall, we show three major findings: (i) APCCs are common in normal adrenals, (ii) APCCs harbor somatic mutations known to cause excess aldosterone production, and (iii) the mutation spectrum of aldosteronedriving mutations is different in APCCs from that seen in APA. These results provide molecular support for APCC as a precursor of PA.primary aldosteronism | aldosterone | adrenal | somatic mutations | aldosterone-producing cell cluster P rimary aldosteronism (PA) accounts for 8% of hypertension and is the most common adrenal disease (1-4). PA patients can be classified into those with aldosterone-producing adenomas (APAs), idiopathic hyperaldosteronism, or familial hyperaldosteronism (FH), which is further divided into FH types 1-3 (FHI-FHIII) (5). In 1992, FHI was shown to result from a gene fusion of cytochrome P450, family 11, subfamily B, polypeptide 2 (CYP11B2: aldosterone synthase) and cytochrome P450, family 11, subfamily B, polypeptide 1 (CYP11B1; cortisol synthase) that resulted in zona fasciculata (ZF) expression of CYP11B2 and excess aldosterone production (6). For almost two decades after the original report, no other genetic abnormalities were identified in the other forms of PA.First reported in 2011, exome sequencing identified a series of germ-line and somatic mutations in genes that altered adrenal cell intracellular Ca 2+ in PA. The most common mutations are somatic mutations of the gene encoding the potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5)...

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Section: Methodsmentioning

confidence: 99%

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

Nishimoto

Tomlins

Kuick

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

269

273

View full text Add to dashboard Cite

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“…Whole genome raw mRNA expression data of 164 tumour (97 ACA and 67 ACC) and 18 NA samples from Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo) and ArrayExpress (http://www.ebi.ac.uk) were collected (Ye et al, 2007;de Reynie`s et al, 2009, Giordano et al, 2009, To¨mbo¨l et al, 2009, reclassified and analysed (Table 2). Data on hormonal activity were unavailable in the study by de Reynie`s et al, (2009).…”

Section: Methodsmentioning

confidence: 99%

“…Each ANOVA was followed by Tukey's post hoc test for all pairwise multiple comparisons. An unpaired t-test was used for the NA-APA and ACA-ACC comparisons for two studies where only these two groups were examined (Ye et al, 2007;de Reynie`s et al, 2009). Fold change filter was set to 2-fold.…”

Section: Methodsmentioning

confidence: 99%

Meta-analysis of adrenocortical tumour genomics data: novel pathogenic pathways revealed

et al. 2010

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“…Although an overexpression of LH and/or GNRH receptors (LHR and GNRHR) has been demonstrated in some APA (6,7), less is known about the aldosterone response to in vivo GNRH or LH in these patients (8).…”

Section: Introductionmentioning

confidence: 99%

A case of primary aldosteronism in pregnancy: do LH and GNRH receptors have a potential role in regulating aldosterone secretion?

Albiger¹,

Sartorato²,

Mariniello³

et al. 2011

European Journal of Endocrinology

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Objective: The mechanisms inducing steroidogenesis in primary aldosteronism (PA) remain poorly defined. It was recently demonstrated that some G-protein-coupled receptors are abnormally expressed in aldosterone-producing adenomas (APA). We evaluated the potential role of LH and GNRH receptors (LHR (or LHCGR) and GNRHR) in regulating aldosterone secretion in a patient with APA arising during pregnancy (index case) and in a subset of other patients with PA. Patients and methods: GNRH test was performed in the index case, 11 other PA, and 5 controls. GNRHR and LHR expressions were examined in 23 APA and 6 normal tissues. Results: Aldosterone response increased significantly (114%) in the index case after GNRH test was performed preoperatively, while it was blunted after adrenalectomy. Aldosterone also increased after human chorionic gonadotropin and triptorelin stimulation. A partial aldosterone response to GNRH was observed in other 7/11 PA, while a significant response was observed in two patients. Controls did not respond to GNRH test. GNRHR was overexpressed and LHR expression was moderate in the APA tissue from the index case. Moreover, LHR was found in normal adrenals and overexpressed in 6/22 APA. GNRHR was overexpressed in 6/22 APA, 2 of them with a 95-and 109-fold higher expression than normal. A correlation between the clinical and molecular findings was observed in five out of seven patients. Conclusion: We describe a case of PA diagnosed during pregnancy, which appeared to correlate with aberrant LHR and GNRHR expression. Our findings suggest that a subset of patients with PA has aberrant LHR and GNRHR expression, which could modulate aldosterone secretion.

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G-protein-coupled receptors in aldosterone-producing adenomas: a potential cause of hyperaldosteronism

Cited by 106 publications

References 69 publications

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

Meta-analysis of adrenocortical tumour genomics data: novel pathogenic pathways revealed

A case of primary aldosteronism in pregnancy: do LH and GNRH receptors have a potential role in regulating aldosterone secretion?

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