A somatic mutation in CLCN2 identified in a sporadic aldosterone-producing adenoma

Dutta, Ravi Kumar; Arnesen, Thomas; Heie, Anette; Walz, Martin K.; Alesina, Pier Francesco; Söderkvist, Peter; Gimm, Oliver

doi:10.1530/eje-19-0377

Cited by 61 publications

(39 citation statements)

References 14 publications

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“…Scholl et al studied the original kindred first described by Stowasser in 2018 and identified a gain-of-function early-onset germline variant in CLCN2 (p.R172Q) [ 28 ], in addition to 4 new rare germline CLCN2 variants (p.M22K, p.Y26N, p.K362del, and p.S865R) [ 28 ]. Concurrently, Fernandes-Rosa and colleagues identified a de novo germline CLCN2 mutation in a 9-year-old patient (p.G24D) [ 27 ] that was similar to the somatic APA mutation recently described by Dutta et al [ 31 ] as well as one of the somatic mutations reported in our study. Both groups performed functional studies wherein electrophysiological experiments in H295R-S2 and HEK293 cells transfected with wild-type and mutant CLCN2 demonstrated that the mutations caused increased activation of the Cl – channels leading to depolarization of the cell membrane and subsequent opening of the voltage-dependent Ca 2+ channels, confirming a gain-of-function mechanism.…”

Section: Discussionsupporting

confidence: 86%

Identification of Somatic Mutations in CLCN2 in Aldosterone-Producing Adenomas

Rege

Nanba

Blinder

et al. 2020

Journal of the Endocrine Society

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Somatic mutations driving aldosterone production have been identified in approximately 90% of aldosterone-producing adenomas (APAs) using an aldosterone synthase (CYP11B2) immunohistochemistry (IHC)-guided DNA sequencing approach. In the present study, using CYP11B2-guided whole-exome sequencing (WES) and targeted amplicon sequencing, we detected 2 somatic variants in CLCN2 in 2 APAs that were negative for currently known aldosterone-driver mutations. The CLCN2 gene encodes the voltage-gated chloride channel ClC-2. CLCN2 germline variants have previously been shown to cause familial hyperaldosteronism type II. Somatic mutations in CLCN2 were identified in 2 of 115 APAs, resulting in a prevalence of 1.74%. One of the CLCN2 somatic mutations (c.G71A,p.G24D) was identical to a previously described germline variant causing early-onset PA, but was present only as a somatic mutation. The second CLCN2 mutation, which affects the same region of the gene, has not been reported previously (c.64-2_74del). These findings prove that WES of CYP11B2-guided mutation-negative APAs can help determine rarer genetic causes of sporadic PA.

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Section: Discussionsupporting

confidence: 86%

Identification of Somatic Mutations in CLCN2 in Aldosterone-Producing Adenomas

Rege

Nanba

Blinder

et al. 2020

Journal of the Endocrine Society

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“…It was the first time that implication of a chloride channel was shown in the regulation of aldosterone production. A recent study also found 1 somatic mutation in CLCN2 , after screening 80 apparently sporadic APAs, in a male patient with PA, which was cured after surgery of its small adenoma [ 103 ].…”

Section: Benign Adrenal Tumors Associated With Primary Hyperaldostmentioning

confidence: 99%

Molecular Basis of Primary Aldosteronism and Adrenal Cushing Syndrome

Vaduva

Bonnet

Bertherat

2020

Journal of the Endocrine Society

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This review reports the main molecular alterations leading to development of benign cortisol and/or aldosterone secreting adrenal tumors. Causes of adrenal Cushing can be divided in two groups: multiple bilateral tumors or adenomas secreting cortisol. Bilateral causes are mainly Primary Pigmented Nodular Adrenocortical Disease (PPNAD), most of the time due to PRKAR1A germline inactivating mutations, and Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH), that can be caused in some rare syndromic cases by germline inactivating mutations of MEN1, APC and FH and of ARMC5 in isolated forms. PRKACA somatic activating mutations are the main alterations in unilateral cortisol producing adenomas (CPA). In primary hyperaldosteronism (PA), familial forms were identified in 1-5% of cases: familial hyperaldosteronism type I (FH-I) due to a chimeric CYP11B1/CYP11B2 hybrid gene, FH-II due to CLCN-2 germline mutations, FH-III due to KCNJ5 germline mutations, FH-IV due to CACNA1H germline mutations and PA, seizures and neurological abnormalities (PASNA) syndrome due to CACNA1D germline mutations. Several somatic mutations have been found in aldosterone producting adenomas (APAs) in KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1 genes.

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“…β-Catenin (CTNNB1) mutations were also identified in a small percentage of APA and a recent study suggests that these mutations may be associated with the process of tumorigenesis rather than direct activation of aldosterone production [29]. Recent studies have demonstrated a small percentage of APA harboring somatic mutations in the voltage-gated chloride channel type 2 (CLCN2) [30] and the calcium channel-gated channel subunit alpha 1H (CAC-NA1H), which were originally shown to cause germline PA [31][32][33][34]. Recent application of aldosterone synthase (CYP11B2)-guided cap-ture of APA followed by higher depth gene-targeted NGS suggests that greater than 90 % of APA have aldosterone-driver mutations [24,26].…”

Section: Overview Of Primary Aldosteronism (Pa)mentioning

confidence: 99%

The Potential Role of Aldosterone-Producing Cell Clusters in Adrenal Disease

Lim

Rainey

2020

Horm Metab Res

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Primary aldosteronism (PA) is the most common cause of secondary hypertension. The hallmark of PA is adrenal production of aldosterone under suppressed renin conditions. PA subtypes include adrenal unilateral and bilateral hyperaldosteronism. Considerable progress has been made in defining the role for somatic gene mutations in aldosterone-producing adenomas (APA) as the primary cause of unilateral PA. This includes the use of next-generation sequencing (NGS) to define recurrent somatic mutations in APA that disrupt calcium signaling, increase aldosterone synthase (CYP11B2) expression, and aldosterone production. The use of CYP11B2 immunohistochemistry on adrenal glands from normal subjects, patients with unilateral and bilateral PA has allowed the identification of CYP11B2-positive cell foci, termed aldosterone-producing cell clusters (APCC). APCC lie beneath the adrenal capsule and like APA, many APCC harbor somatic gene mutations known to increase aldosterone production. These findings suggest that APCC may play a role in pathologic progression of PA. Herein, we provide an update on recent research directed at characterizing APCC and also discuss the unanswered questions related to the role of APCC in PA.

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A somatic mutation in CLCN2 identified in a sporadic aldosterone-producing adenoma

Cited by 61 publications

References 14 publications

Identification of Somatic Mutations in CLCN2 in Aldosterone-Producing Adenomas

Identification of Somatic Mutations in CLCN2 in Aldosterone-Producing Adenomas

Molecular Basis of Primary Aldosteronism and Adrenal Cushing Syndrome

The Potential Role of Aldosterone-Producing Cell Clusters in Adrenal Disease

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