WNT/β-catenin signalling is activated in aldosterone-producing adenomas and controls aldosterone production

Berthon, Annabel; Drelon, Coralie; Ragazzon, Bruno; Boulkroun, Sheerazed; Tissier, Frédérique; Amar, Laurence; Samson-Couterie, Benoît; Zennaro, Maria-Christina; Plouin, Pierre‐François; Skah, Seham; Plateroti, Michelina; Lefebvre, Henri; Sahut‐Barnola, Isabelle; Batisse-Lignier, Marie; Assié, Guillaume; Lefrançois‐Martinez, Anne‐Marie; Bertherat, Jérôme; Martinez, Antoine; Val, Pierre

doi:10.1093/hmg/ddt484

Cited by 168 publications

(166 citation statements)

References 65 publications

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“…Familial adenomatous polyposis coli and mutations of APC " Activation of the Wnt/b-catenin signaling pathway is involved in adrenal tumors, especially non-cortisolproducing adenomas and adrenocortical carcinomas (31). Patients with familial adenomatous polyposis (FAP) (OMIM #175100) present multiple colonic polyps and an increased risk of early colon carcinomas and various adrenocortical tumors, including non-functional cortisol producing adenoma, adrenocortical cancer (31) and bilateral macronodular adrenal hyperplasia (10,32).…”

Section: Multiple Tumors Syndromes Associated With Pbmahmentioning

confidence: 99%

Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

Drougat

Espiard

Bertherat

2015

European Journal of Endocrinology

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Long-term consequences of cortisol excess are frequent despite appropriate treatment after cure of Cushing's syndrome. This might be due to diagnostic delay, often difficult to reduce in rare diseases. The identification of a genetic predisposing factor might help to improve early diagnosis by familial screening. Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Hypercortisolism in PBMAH is most often diagnosed between the fifth and sixth decades of life. The bilateral nature of the adrenocortical tumors and the occurrence of rare clear familial forms suggest a genetic origin. Indeed, a limited subset of PBMAH can be observed as part of multiple tumors syndromes due to alterations of the APC, Menin or Fumarate Hydratase genes. Rare variants of the phosphodiesterases PDE11A have been associated with PBMAH. The recent identification of ARMC5 germline alterations in 25-50% of PBMAH patients without obvious familial history or associated tumors opens new perspectives. ARMC5 alterations follow the model of a tumor suppressor gene: a first germline inactivating mutation of this 16p located gene is followed by a somatic secondary hit on the other allele (inactivating mutation or allelic loss). Functional studies demonstrate that ARMC5 controls apoptosis and steroid synthesis. The phenotype of index cases patients with the mutation seems more severe than the one of WT index cases. However, phenotype variability within a family is often observed. This review summarizes the genetics of PBMAH, focusing on ARMC5, which offer new perspectives for early diagnosis of Cushing's syndrome.

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Section: Multiple Tumors Syndromes Associated With Pbmahmentioning

confidence: 99%

Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

Drougat

Espiard

Bertherat

2015

European Journal of Endocrinology

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“…One potential mechanism could be the activation of the WNT/b-catenin pathway. Indeed, it has been shown that this pathway is activated in w70% of APA (Boulkroun et al 2011, Berthon et al 2014), that in rare cases somatic activating mutations of CTNN1B, coding for b-catenin, have been described in APA (Azizan et al 2013, Scholl et al 2013 and that constitutive b-catenin activation in the adrenal cortex induces ectopic ZG differentiation and dedifferentiation of the orthotopic ZF, resulting in hyperaldosteronism in 10-month-old mice (Berthon et al 2010). However some of these mice develop malignant characteristics, such as uncontrolled neovascularization and local invasion, a phenotype rarely observed in patients with PA (Berthon et al 2010); it is possible that the levels of b-catenin dosage play a role in the development of specific types of tumors within the adrenal cortex (Berthon et al 2014).…”

Section: Familial Hyperaldosteronism Type IImentioning

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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“…Activation of the β-catenin pathway is restricted to the ZG (Kim et al 2008;Walczak et al 2014), and ectopic expression leads to the activation of ZG markers in ZF cells (Berthon et al 2010). Moreover, β-catenin seems to bind to and control the expression of At1r, a gene specifically expressed within the ZG (Berthon et al 2014). Finally, stochastic deletion of β-catenin using a low-level expressing Sf1-Cre line leads to progressive loss of the adrenal cortex in adult life (Kim et al 2008).…”

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confidence: 99%

The adrenal capsule is a signaling center controlling cell renewal and zonation through Rspo3

Vidal¹,

Sacco²,

Rocha³

et al. 2016

Genes Dev.

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Adrenal glands are zonated endocrine organs that are essential in controlling body homeostasis. How zonation is induced and maintained and how renewal of the adrenal cortex is ensured remain a mystery. Here we show that capsular RSPO3 signals to the underlying steroidogenic compartment to induce β-catenin signaling and imprint glomerulosa cell fate. Deletion of RSPO3 leads to loss of SHH signaling and impaired organ growth. Importantly, Rspo3 function remains essential in adult life to ensure replenishment of lost cells and maintain the properties of the zona glomerulosa. Thus, the adrenal capsule acts as a central signaling center that ensures replacement of damaged cells and is required to maintain zonation throughout life.

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WNT/β-catenin signalling is activated in aldosterone-producing adenomas and controls aldosterone production

Cited by 168 publications

References 65 publications

Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

An update on novel mechanisms of primary aldosteronism

The adrenal capsule is a signaling center controlling cell renewal and zonation through Rspo3

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