Novel<i>KCNJ5</i>Mutations in Sporadic Aldosterone-Producing Adenoma Reduce Kir3.4 Membrane Abundance

Cheng, Chih Jen; Sung, Chih Chien; Wu, Sing-Yung; Lin, Yn-Hwang; Sytwu, Huey Kang; Huang, Chou Long; Lin, Shih Hua

doi:10.1210/jc.2014-3009

Cited by 44 publications

(38 citation statements)

References 28 publications

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“…However, for non-pore mutants the mechanism could be different. Remarkably, GIRK4 expression is actually decreased in aldosterone-producing adenomas, for some mutations rather severely (Cheng et al, 2015;FernandesRosa et al, 2015). Also, even with pore mutants of GIRK4, no severe cardiac phenotype is observed (as it would be expected from changes in K + /Na + selectivity); elevated risk of cardiac complications in patients with PA is indirect, due to hypertension (Adachi et al, 2014;Al-Salameh et al, 2014).…”

Section: Adrenal Glandmentioning

confidence: 99%

The Roles of Gβγ and Gα in Gating and Regulation of GIRK Channels

Dascal

Kahanovitch

2015

International Review of Neurobiology

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Section: Adrenal Glandmentioning

confidence: 99%

The Roles of Gβγ and Gα in Gating and Regulation of GIRK Channels

Dascal

Kahanovitch

2015

International Review of Neurobiology

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“…The prevalence of somatic KCNJ5 mutations is not so high in another Asian population. 30 International multicenter studies may help reduce selection bias. In addition, long-term follow-up has not been accomplished, and we are unable to predict prognosis based on KCNJ5 mutations at present.…”

Section: Limitationsmentioning

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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“…Although KCNJ5 mRNA expression is not affected by mutational status, at the protein level, decreased GIRK4 expression in APA compared with peritumoral ZG was observed in APA with KCNJ5 mutations compared to non-mutated APA or those with other mutations , Cheng et al 2015, Fernandes-Rosa et al 2015a. KCNJ5 mutations were associated neither with specific adrenal cortex remodeling nor specific transcriptional profiles (Boulkroun et al 2012.…”

Section: Mutations Affecting Cell Membrane Potentialmentioning

confidence: 82%

“…In addition to affecting K + cell permeability, two KCNJ5 mutations (p.Arg115Trp and p.Glu246Gly) decreased GIRK4 wt currents when coexpressed in HEK cells and altered the membrane abundance of the channels, suggesting that reduced GIRK4 in cell surface may lead to inappropriate hypersecretion of aldosterone and formation of adrenal adenoma (Cheng et al 2015), although this is not the case for other mutations (Murthy et al 2012). Although KCNJ5 mRNA expression is not affected by mutational status, at the protein level, decreased GIRK4 expression in APA compared with peritumoral ZG was observed in APA with KCNJ5 mutations compared to non-mutated APA or those with other mutations , Cheng et al 2015, Fernandes-Rosa et al 2015a.…”

Section: Mutations Affecting Cell Membrane Potentialmentioning

confidence: 99%

Somatic and inherited mutations in primary aldosteronism

Fernandes-Rosa

Boulkroun

Zennaro

2017

Journal of Molecular Endocrinology

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Primary aldosteronism (PA), the most common form of secondary hypertension, is caused in the majority of cases by unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. Over the past few years, somatic mutations in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 have been proven to be associated with APA development, representing more than 50% of sporadic APA. The identification of these mutations has allowed the development of a model for APA involving modification on the intracellular ionic equilibrium and regulation of cell membrane potential, leading to autonomous aldosterone overproduction. Furthermore, somatic CTNNB1 mutations have also been identified in APA, but the link between these mutations and APA development remains unknown. The sequence of events responsible for APA formation is not completely understood, in particular, whether a single hit or a double hit is responsible for both aldosterone overproduction and cell proliferation. Germline mutations identified in patients with early-onset PA have expanded the classification of familial forms (FH) of PA. The description of germline KCNJ5 and CACNA1H mutations has identified FH-III and FH-IV based on genetic findings; germline CACNA1D mutations have been identified in patients with very early-onset PA and severe neurological abnormalities. This review summarizes current knowledge on the genetic basis of PA, the association of driver gene mutations and clinical findings and in the contribution to patient care, plus the current understanding on the mechanisms of APA development.

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NovelKCNJ5Mutations in Sporadic Aldosterone-Producing Adenoma Reduce Kir3.4 Membrane Abundance

Cited by 44 publications

References 28 publications

The Roles of Gβγ and Gα in Gating and Regulation of GIRK Channels

The Roles of Gβγ and Gα in Gating and Regulation of GIRK Channels

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

Somatic and inherited mutations in primary aldosteronism

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