Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause

Zhou, Junhua; Azizan, Elena; Cabrera, Claudia; Fernandes-Rosa, Fábio Luiz; Boulkroun, Sheerazed; Argentesi, Giulia; Cottrell, Emily; Amar, Laurence; Wu, Xiaozhen; O'Toole, Sam; Goodchild, Emily; Marker, Alison; Senanayake, Russell; Garg, Shivam; Åkerström, Tobias; Backman, Samuel; Jordan, Suzanne; Polubothu, Satyamaanasa; Berney, Daniel M.; Gluck, Anna; Lines, Kate E; Thakker, Rajesh; Tuthill, Antoinette; Joyce, Caroline; Kaski, Juan Pablo; Karet, Fiona E.; Metherell, Lou; Teo, Ada; Gurnell, Mark; Parvanta, Laila; Drake, William M; Wozniak, Eva; Klinzing, David C.; Kuan, Jyn Ling; Tiang, Zenia; Sanchez, Celso E Gomez; Hellman, Per; Foo, Roger; Mein, Charles A.; Kinsler, Veronica A.; Björklund, Peyman; Storr, Helen L; Zennaro, Maria‐Christina; Mj, Brown

doi:10.1038/s41588-021-00906-y

Cited by 51 publications

(50 citation statements)

References 79 publications

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“…Concurrent mutations in CTNNB1 and GNA11 / Q were associated with increased expression of luteinizing hormone/choriogonadotropin receptor ( LHCGR ), potentially explaining an association with pregnancy. 33 In mice, expression of a Ctnnb1 gain-of-function allele to the zona glomerulosa leads to a block of transdifferentiation of zona glomerulosa cells into zona fasciculata cells, resulting in progressive hyperplastic expansion of the zona glomerulosa and increased aldosterone levels. 34 This observation suggests that CTNNB1 mutations may act primarily by increasing the number of aldosterone-producing cells, which may be sufficient to cause PA once tumors are large enough.…”

Section: Somatic Mutations In Apasmentioning

confidence: 99%

Genetics of Primary Aldosteronism

Scholl

2022

Hypertension

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Primary aldosteronism is considered the commonest cause of secondary hypertension. In affected individuals, aldosterone is produced in an at least partially autonomous fashion in adrenal lesions (adenomas, [micro]nodules or diffuse hyperplasia). Over the past decade, next-generation sequencing studies have led to the insight that primary aldosteronism is largely a genetic disorder. Sporadic cases are due to somatic mutations, mostly in ion channels and pumps, and rare cases of familial hyperaldosteronism are caused by germline mutations in an overlapping set of genes. More than 90% of aldosterone-producing adenomas carry somatic mutations in K + channel Kir3.4 ( KCNJ5 ), Ca 2+ channel Ca V 1.3 ( CACNA1D ), alpha-1 subunit of the Na + /K + ATPase ( ATP1A1 ), plasma membrane Ca 2+ transporting ATPase 3 ( ATP2B3 ), Ca 2+ channel Ca V 3.2 ( CACNA1H ), Cl − channel ClC-2 ( CLCN2 ), β-catenin ( CTNNB1 ), and G - protein subunits alpha q/11 ( GNAQ/11 ). Mutations in some of these genes have also been identified in aldosterone-producing (micro)nodules, suggesting a disease continuum from a single cell, acquiring a somatic mutation, via a nodule to adenoma formation, and from a healthy state to subclinical to overt primary aldosteronism. Individual glands can have multiple such lesions, and they can occur on both glands in bilateral disease. Familial hyperaldosteronism, typically with early onset, is caused by germline mutations in steroid 11-beta hydroxylase / aldosterone synthase ( CYP11B1/2 ), CLCN2 , KCNJ5 , CACNA1H , and CACNA1D .

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Section: Somatic Mutations In Apasmentioning

confidence: 99%

Genetics of Primary Aldosteronism

Scholl

2022

Hypertension

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“…The gain of function mutation in GNA11, a gene coding the α subunit of the G protein, and its close homologue GNAQ have been identified in patients with APA. However, these mutations seem to be clinically silent without a codriver mutation in CTNNB1, a gene encoding catenin β1 (Zhou et al, 2021). The importance of aberrant activation of Wnt/β-catenin signaling pathways in APA is well characterized (Wang et al, 2017).…”

Section: Angiotensin IImentioning

confidence: 99%

Aldosterone-Regulated Sodium Transport and Blood Pressure

2022

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Aldosterone is a major mineralocorticoid steroid hormone secreted by glomerulosa cells in the adrenal cortex. It regulates a variety of physiological responses including those to oxidative stress, inflammation, fluid disruption, and abnormal blood pressure through its actions on various tissues including the kidney, heart, and the central nervous system. Aldosterone synthesis is primarily regulated by angiotensin II, K+ concentration, and adrenocorticotrophic hormone. Elevated serum aldosterone levels increase blood pressure largely by increasing Na+ re-absorption in the kidney through regulating transcription and activity of the epithelial sodium channel (ENaC). This review focuses on the signaling pathways involved in aldosterone synthesis and its effects on Na+ reabsorption through ENaC.

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“…The presence of somatic mutations in APMs suggests that co-driver mutations are necessary in order to promote APA formation. In line with this two-hit theory, co-existence of CTNNB1 with GNAQ or GNA11 mutations was described in APAs, whereas solitary GNAQ / GNA11 mutations were identified in the adjacent hyperplastic zona glomerulosa of the double mutant APAs [ 12 ]. Similarly, the occurrence of KCNJ5 mutations in adrenals from patients with germline APC Regulator of WNT Signaling Pathway ( APC ) mutations has been previously described [ 38 ].…”

Section: Resultsmentioning

confidence: 97%

“…In one recent study, MC2R expression correlated positively with that of AGTR1 in APAs harboring KCNJ5 and CACNA1D mutations, whereas MC2R expression correlated positively with Melanocortin 2 Receptor Accessory Protein ( MRAP ) only in ATP1A1 - and ATP2B3 -mutated APAs [ 72 ]. Moreover, LHCG - and GNRH -receptor upregulation were both correlated with APAs harboring CTNNB1 mutations [ 12 , 49 ]. On the contrary, Arginine vasopressin receptor 1A ( AVPR1A ) and Prostaglandin F Receptor ( PTGFR ) were significantly downregulated in APAs [ 70 ].…”

Section: Resultsmentioning

confidence: 99%

“…β-catenin 1 ( CTNNB1 ) mutations, identified in a small proportion of APAs, cause constitutive activation of β-catenin and are considered to directly promote CYP11B2 synthesis [ 11 ]. More recently, co-existence of CTNNB1 with G Protein Subunit Alpha Q ( GNAQ )/G Protein Subunit Alpha 11 ( GNA11 ) mutations was documented in 59% of APAs [ 12 ]. Rarely, Protein Kinase cAMP-Activated Catalytic Subunit Alpha ( PRKACA ), sporadic Calcium Voltage-Gated Channel Subunit Alpha1 H ( CACNA1H ) and Chloride Voltage-Gated Channel 2 ( CLCN2 ) mutations have also been identified in sporadic APAs [ 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomics, Epigenetics, and Metabolomics of Primary Aldosteronism

Spyroglou

Piaditis

Kaltsas

et al. 2021

Cancers

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Introduction: Primary aldosteronism (PA) is the most common cause of endocrine hypertension, mainly caused by aldosterone-producing adenomas or hyperplasia; understanding its pathophysiological background is important in order to provide ameliorative treatment strategies. Over the past several years, significant progress has been documented in this field, in particular in the clarification of the genetic and molecular mechanisms responsible for the pathogenesis of aldosterone-producing adenomas (APAs). Methods: Systematic searches of the PubMed and Cochrane databases were performed for all human studies applying transcriptomic, epigenetic or metabolomic analyses to PA subjects. Studies involving serial analysis of gene expression and microarray, epigenetic studies with methylome analyses and micro-RNA expression profiles, and metabolomic studies focused on improving understanding of the regulation of autonomous aldosterone production in PA were all included. Results: In this review we summarize the main findings in this area and analyze the interplay between primary aldosteronism and several signaling pathways with differential regulation of the RNA and protein expression of several factors involved in, among others, steroidogenesis, calcium signaling, and nuclear, membrane and G-coupled protein receptors. Distinct transcriptomic and metabolomic patterns are also presented herein, depending on the mutational status of APAs. In particular, two partially opposite transcriptional and steroidogenic profiles appear to distinguish APAs carrying a KCNJ5 mutation from all other APAs, which carry different mutations. Conclusions: These findings can substantially contribute to the development of personalized treatment in patients with PA.

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Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause

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Cited by 51 publications

References 79 publications

Genetics of Primary Aldosteronism

Genetics of Primary Aldosteronism

Aldosterone-Regulated Sodium Transport and Blood Pressure

Transcriptomics, Epigenetics, and Metabolomics of Primary Aldosteronism

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