Primary Aldosteronism and<i>ARMC5</i>Variants

Zilbermint, Mihail; Xekouki, Paraskevi; Faucz, Fábio R.; Berthon, Annabel; Gkourogianni, Alexandra; Schernthaner-Reiter, Marie Helene; Batsis, Maria; Sinaii, Ninet; Quezado, Martha; Merino, María J.; Hodes, Aaron; Abraham, Smita Baid; Libé, Rossella; Assié, Guillaume; Espiard, Stéphanie; Drougat, Ludivine; Ragazzon, Bruno; Davis, Adam R.; Gebreab, Samson Y.; Neff, Ryan; Kebebew, Electron; Bertherat, Jérôme; Lodish, Maya; Stratakis, Constantine A.

doi:10.1210/jc.2014-4167

“…To determine if such germ-line variants may predispose to APCC accumulation, APCC score, or mutation status of genes somatically altered in APA, we performed Sanger sequencing of the ARMC5 coding sequence on germ-line DNA isolated from five adrenals with the highest APCC scores (DAN8, -11, -15, -21, and -26). Only one adrenal (DAN15) had a nonsynonymous alteration (P507L), which was previously reported as benign based on in silico analysis (34). Hence, although our results do not support a role for germ-line variants in ARMC5 driving APCC accumulation, determining genetic associations with APCC development is an important area for future research.…”

Section: Discussionmentioning

confidence: 51%

“…Recently, PA was found to associate with germ-line mutations in armadillo repeat containing 5 (ARMC5) (34). To determine if such germ-line variants may predispose to APCC accumulation, APCC score, or mutation status of genes somatically altered in APA, we performed Sanger sequencing of the ARMC5 coding sequence on germ-line DNA isolated from five adrenals with the highest APCC scores (DAN8, -11, -15, -21, and -26).…”

Section: Discussionmentioning

confidence: 99%

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

Nishimoto

¹

,

Tomlins

²

,

Kuick

³

et al. 2015

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

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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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“…The investigation of a cohort of 56 patients with primary hyperaldosteronism showed 10.7% of ARMC5 variants predicted pathogenic by in silico analysis in African-American patients. Two of these patients had bilateral adrenal hyperplasia and co-secretion of aldosterone and cortisol (41). Whether this applies to other populations remains to be demonstrated.…”

Section: Armc5 Mutations and Phenotype In Pbmah "mentioning

confidence: 94%

“…Another interesting observation is that ARMC5-mutated patients have hypertension more often than WT patients. A more severe hypercortisolism is probably one of the major explanations, but it has been recently suggested that ARMC5 mutation could favor hypertension with low renin hyperaldosteronism in the African-American population (41). The investigation of a cohort of 56 patients with primary hyperaldosteronism showed 10.7% of ARMC5 variants predicted pathogenic by in silico analysis in African-American patients.…”

Section: Armc5 Mutations and Phenotype In Pbmah "mentioning

confidence: 99%

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

Drougat

¹

,

Espiard

²

,

Bertherat

³

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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Molecular Genetics of Hyperaldosteronism

Scholl

¹

2017

Encyclopedia of Life Sciences

0

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In primary aldosteronism, the adrenal gland produces excessive amounts of the steroid hormone aldosterone, which causes hypertension. Common causes are aldosterone‐producing adenomas (benign tumours) and bilateral adrenal hyperplasia. The majority of aldosterone‐producing adenomas carry somatic mutations in known disease genes. These include KCNJ5 (a potassium channel), CACNA1D (a calcium channel) and ATP1A1 and AT2B3 (ATPase subunits). These mutations either directly or indirectly cause increased intracellular calcium levels, which lead to increased aldosterone production and proliferation. Mutations in CTNNB1 (beta‐catenin) are rare. The molecular mechanisms underlying bilateral adrenal hyperplasia are largely unknown, with the exception of rare forms of familial hyperaldosteronism (FH). FH‐I, ‐III and ‐IV are caused by germ line mutations in CYP11B2 (aldosterone synthase), KCNJ5 and CACNA1H (another calcium channel), respectively, and a syndrome that includes neurologic abnormalities is due to germ line mutations in CACNA1D . These observations suggest pathways for the development of novel diagnostic and therapeutic strategies in primary aldosteronism. Key Concepts Primary aldosteronism is the most common cause of secondary hypertension, caused by aldosterone‐producing adenoma or bilateral adrenal hyperplasia. Recent exome sequencing studies have identified the genetic basis of the majority of aldosterone‐producing adenomas. Somatic mutations in the potassium channel KCNJ5 explain about 40% of aldosterone‐producing adenomas. Mutations in KCNJ5 are associated with female gender, early onset and larger tumour size. Other somatic mutations in aldosterone‐producing adenomas affect the CACNA1D , ATP1A1 , ATP2B3 and CTNNB1 genes. The shared common final pathway of somatic mutations in aldosterone‐producing adenomas is increased calcium signalling, which causes excessive aldosterone production and proliferation. The pathophysiology of sporadic bilateral adrenal hyperplasia is largely unknown. Rare forms of familial hyperaldosteronism (FH) include FH‐I, ‐III and ‐IV, caused by germ line mutations in CYP11B2 , KCNJ5 and CACNA1H , respectively, and FH‐II, whose genetic basis remains unknown. The identification of the molecular mechanisms of primary aldosteronism suggests pathways for the development of novel diagnostic and therapeutic strategies.

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Primary Aldosteronism andARMC5Variants

Cited by 94 publications

References 55 publications

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

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

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

Molecular Genetics of Hyperaldosteronism

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