Understanding primary aldosteronism: impact of next generation sequencing and expression profiling

Monticone, Silvia; Else, Tobias; Mulatero, Paolo; Williams, Tracy Ann; Rainey, William E.

doi:10.1016/j.mce.2014.09.015

Cited by 48 publications

(39 citation statements)

References 105 publications

(154 reference statements)

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“…KCNJ5 encodes the G protein-activated inward rectifier potassium channel GIRK4 (alternative protein name KIR3.4). All KCNJ5 mutations identified so far in APA, as well as different germline mutations identified in familial hyperaldosteronism type III (FH3) (see below), are located in exon 2; the most frequent of them are p.Gly151Arg and p.Leu168Arg, but less frequent ones located nearby have also been described (for an extensive list of identified mutations, see Gomez-Sanchez (2014) and Monticone et al (2014)). All these mutations are located near or within the selectivity filter of GIRK4, which allows selective passage of potassium ions through the channel pore, and affect the ion selectivity of the channel.…”

Section: Somatic Mutations In Apamentioning

confidence: 99%

An update on novel mechanisms of primary aldosteronism

Zennaro¹,

Boulkroun²,

Fernandes-Rosa³

2014

Journal of Endocrinology

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Primary aldosteronism (PA) is the most common and curable form of secondary hypertension. It is caused in the majority of cases by either unilateral aldosterone overproduction due to an aldosterone-producing adenoma (APA) or by bilateral adrenal hyperplasia. Recent advances in genome technology have allowed researchers to unravel part of the genetic abnormalities underlying the development of APA and familial hyperaldosteronism. Recurrent somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and ATPases (ATP1A1 and ATP2B3) regulating intracellular ionic homeostasis and cell membrane potential have been identified in APA. Similar germline mutations of KCNJ5 were identified in a severe familial form of PA, familial hyperaldosteronism type 3 (FH3), whereas de novo germline CACNA1D mutations were found in two cases of hyperaldosteronism associated with a complex neurological disorder. These results have allowed a pathophysiological model of APA development to be established. This model involves modifications in intracellular ionic homeostasis and membrane potential, accounting for w50% of all tumors, associated with specific gender differences and severity of PA. In this review, we describe the different genetic abnormalities associated with PA and discuss the mechanisms whereby they lead to increased aldosterone production and cell proliferation. We also address some of the foreseeable consequences that genetic knowledge may contribute to improve diagnosis and patient care.

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Section: Somatic Mutations In Apamentioning

confidence: 99%

An update on novel mechanisms of primary aldosteronism

Zennaro¹,

Boulkroun²,

Fernandes-Rosa³

2014

Journal of Endocrinology

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“…7 In a large European study, the combined prevalence of APA mutations in these 4 genes was found to be 54% with 38% Abstract-Primary aldosteronism comprises 2 main subtypes: unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia. Somatic KCNJ5 mutations are found in APA at a prevalence of around 40% that drive and sustain aldosterone excess.…”

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confidence: 99%

Genotype-Specific Steroid Profiles Associated With Aldosterone-Producing Adenomas

et al. 2016

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P rimary aldosteronism (PA) is the leading cause of secondary hypertension with a prevalence of 4.3% in the general hypertensive population and 9.5% of patients referred to hypertension units. 1 The diagnosis of PA is fundamental because these patients are at an increased risk of cardiovascular and cerebrovascular complications and metabolic syndrome compared with patients with primary hypertension and similar cardiovascular risk profiles. [2][3][4][5] The underlying cause of PA in the majority of patients is either bilateral adrenal hyperplasia (BAH, also called idiopathic hyperaldosteronism) or unilateral aldosterone-producing adenoma (APA). These subtypes must be differentiated to permit a targeted therapeutic strategy: surgical removal of APA or pharmacological treatment of BAH with mineralocorticoid receptor antagonists. Adrenal venous sampling (AVS) is the gold standard to localize the source of aldosterone excess and to discriminate between unilateral and bilateral forms of the disease. However, AVS is a technically demanding and invasive procedure requiring a dedicated radiologist. The reliable differentiation of APA and BAH by an alternative technique could potentially circumvent the requirement of AVS in patients with BAH that account for around two thirds of all cases of PA. 6 Subsequently, for the APA subtype, both clinician and patient would be highly motivated to perform/undergo AVS to confirm unilateral PA and define the side of aldosterone excess before adrenalectomy.Somatic mutations have been identified in APA in 4 genes (KCNJ5, ATP1A1, ATP2B3, and CACNA1D) to date that all lead to an increase in constitutive aldosterone production. 7 In a large European study, the combined prevalence of APA mutations in these 4 genes was found to be 54% with 38% Abstract-Primary aldosteronism comprises 2 main subtypes: unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia. Somatic KCNJ5 mutations are found in APA at a prevalence of around 40% that drive and sustain aldosterone excess. Somatic APA mutations have been described in other genes (CACNA1D, ATP1A1, and ATP2B3) albeit at a lower frequency. Our objective was to identify genotype-specific steroid profiles in adrenal venous (AV) and peripheral venous (PV) plasma in patients with APAs. We measured the concentrations of 15 steroids in AV and PV plasma samples by liquid chromatography-tandem mass spectrometry from 79 patients with confirmed unilateral primary aldosteronism. AV sampling lateralization ratios of steroids normalized either to cortisol or to DHEA+androstenedione were also calculated. 9 Intriguingly, mutations in ATP1A1, ATP2B3, and CACNA1D that stimulate aldosterone production have been identified recently in aldosterone-producing cell clusters of normal adrenal glands from kidney donors; in contrast, mutations in KCNJ5 were not detected. 10In this study, we used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the steroid profiles in adrenal venous (AV) and peripheral venous (PV) plasma samples ...

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“…1 The breakthrough was the identification of somatic mutations in the potassium channel GIRK4 (encoded by KCNJ5) in aldosterone-producing adenomas (APAs) 2 and the contemporaneous discovery, by the same authors, of a germline mutation responsible for familial hyperaldosteronism type III. 2 This was followed by the identification of further somatic mutations in APAs in 2 ATPases (Na -channel, Cav1.3 (encoded by CACNA1D).…”

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confidence: 99%

“…2 This was followed by the identification of further somatic mutations in APAs in 2 ATPases (Na -channel, Cav1.3 (encoded by CACNA1D). [1][2][3][4][5] The zona glomerulosa cells of the adrenal cortex display a high resting outward potassium current through the GIRK4 potassium channel that contributes to the hyperpolarization of the cell membrane. Most of the GIRK4 mutations identified in APA are located in or within close proximity to the selectivity filter of the K + channel and result in the indiscriminate conductance of Na + that depolarizes the cell membrane and causes the opening of voltage-gated Ca 2+ channels.…”

mentioning

confidence: 99%