Effect of<i>KCNJ5</i>Mutations on Gene Expression in Aldosterone-Producing Adenomas and Adrenocortical Cells

Monticone, Silvia; Hattangady, Namita G.; Nishimoto, Katsutaro; Mantero, Franco; Rubin, Beatrice; Cicala, Maria Verena; Pezzani, Raffaele; Auchus, Richard J.; Ghayee, Hans K.; Shibata, Hirotaka; Kurihara, Isao; Williams, Tracy Ann; Giri, Judith G.; Bollag, Roni J.; Edwards, Michael A.; Isales, Carlos M.; Rainey, William E.

doi:10.1210/jc.2011-3132

Cited by 139 publications

(109 citation statements)

References 18 publications

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“…Such approaches may illuminate drivers in ∼65% of APCCs that did not harbor candidate drivers by our panel-based approach. Of interest, no well-supported somatic KCNJ5 mutations were observed in our APCCs subjected to NGS, although mutations in KCNJ5 occur in at least 30% of APAs (7,8,17,21). Given that APCCs in our cohort harbored somatic mutations in CACNA1D (26%) and ATP1A1 (9%), at residues previously reported in APA, APCCs may represent a precursor population of cells that lead to APA with these mutations through unknown mechanisms.…”

Section: Discussionmentioning

confidence: 67%

“…However, both of these ZG/ZF-like cells strongly express CYP11B2, consistent with autonomous aldosterone production in APCCs. Recurrent mutations observed in APA are known to cause aldosterone overproduction in in vitro experiments (8,12); therefore, the existence of these mutations in APCCs supports autonomous aldosterone production. Of note, we identified distinct somatic mutations in individual APCCs from the same adrenal gland, which is in contrast to previously studied APAs that have been reported to harbor a single mutation driving aldosterone production.…”

Section: Discussionmentioning

confidence: 96%

“…Germ-line KCNJ5 mutations were also identified as the cause of FHIII (7, 11). KCNJ5 mutations cause pathologic conductivity of Na + ions, cell depolarization, and increased intracellular Ca 2+ , which results in CYP11B2 expression and aldosterone hypersecretion (7,8,11,12). In addition to KCNJ5 mutations, ATPase, Na + /K + transporting, α1-polypeptide (ATP1A1); ATPase, Ca 2+ -transporting, plasma membrane 3 (ATP2B3), and calcium channel, voltage-dependent, L-type, α1D-subunit (CACNA1D) mutations have been found in an additional ∼15% of APA (10,13,14).…”

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confidence: 99%

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

Nishimoto

Tomlins

Kuick

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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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

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

Nishimoto

Tomlins

Kuick

et al. 2015

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

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269

273

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“…Monticone et al recently reported a study of steroidogenic enzyme mRNA levels in 47 APAs including 5 Japanese patients, and found all 5 cases to have a mutation of the KCNJ5 gene [19]. Although the details for these 5 cases were not reported, Japanese patients with typical APA may have a high prevalence of somatic mutations of the KCNJ5 gene.…”

Section: Expression Of Steroidogenic Enzymes and Kcnj5 Mrna In Patienmentioning

confidence: 99%

KCNJ5 mutations in aldosterone- and cortisol-co-secreting adrenal adenomas [Rapid Communication]

et al. 2012

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“…10,13,14,[18][19][20][21][22] First, somatic KCNJ5 mutations were more common in female than male patients. Second, in the presence of KCNJ5 mutations, larger tumor size, higher urinary aldosterone, higher aldosterone-renin ratio, and lateralization index were observed, which suggested that excess aldosterone was related to the mutated APA.…”

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confidence: 99%

Clinical Characteristics of Somatic Mutations in Chinese Patients With Aldosterone-Producing Adenoma

et al. 2015

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Recent studies have shown that somatic mutations in the KCNJ5, ATP1A1, ATP2B3, and CACNA1D genes are associated with the pathogenesis of aldosterone-producing adenoma. Clinical profile and biochemical characteristics of the mutations in Chinese patients with aldosterone-producing adenoma remain unclear. In this study, we performed DNA sequencing in 168 Chinese patients with aldosterone-producing adenoma and found 129 somatic mutations in KCNJ5, 4 in ATP1A1, 1 in ATP2B3, and 1 in CACNA1D. KCNJ5 mutations were more prevalent in female patients and were associated with larger adenomas, higher aldosterone excretion, and lower minimal serum K + concentration. More interestingly, we identified a novel somatic KCNJ5 mutation (c.445-446insGAA, p.T148-T149insR) that could enhance CYP11B2 mRNA upregulation and aldosterone release. This mutation could also cause membrane depolarization and intercellular Ca 2+ increase. In conclusion, somatic KCNJ5 mutations are conspicuously more popular than mutations of other genes in aldosterone-producing adenomas of Chinese patients. The T148-T149insR mutation in KCNJ5 may influence K + channel selectivity and autonomous aldosterone production.

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Effect ofKCNJ5Mutations on Gene Expression in Aldosterone-Producing Adenomas and Adrenocortical Cells

Abstract: KCNJ5 mutations are prevalent in APA, and our data suggest that these mutations increase expression of CYP11B2 and NR4A2, thus increasing aldosterone production.

Cited by 139 publications

References 18 publications

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

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

KCNJ5 mutations in aldosterone- and cortisol-co-secreting adrenal adenomas [Rapid Communication]

Clinical Characteristics of Somatic Mutations in Chinese Patients With Aldosterone-Producing Adenoma

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