Original Article

Clinical Characteristics of Somatic Mutations in Chinese Patients With Aldosterone-Producing AdenomaNovelty and Significance

Fang-Fang Zheng, Li-Min Zhu, Ai-Fang Nie, Xiao-Ying Li, Jing-Rong Lin, Ke Zhang, Jing Chen, Wen-Long Zhou, Zhou-Jun Shen, Yi-Chun Zhu, Ji-Guang Wang, Ding-Liang Zhu, Ping-Jin Gao
https://doi.org/10.1161/HYPERTENSIONAHA.114.03346
Hypertension. 2015;65:622-628
Originally published January 26, 2015

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Abstract

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 Ca2+ 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.

Introduction

See Editorial Commentary, pp 507–509

Primary aldosteronism (PA), known as the most common cause of endocrine hypertension, accounts for ≈10% of newly diagnosed hypertensive patients.1 It is characterized by the dysregulation of aldosterone production. Compared with essential hypertension patients, PA patients are at higher risk of cardio-cerebrovascular complications that deserves more attention.2–5 The Endocrine Society recommends screening for PA in patients with drug-resistant hypertension, hypokalemia, and so on.6 PA comprises both sporadic and familial forms.6,7 Aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia are the major causes of sporadic PA.6 It is of value to detect the molecular mechanisms of APA, a possibly curable disease, because adrenalectomy could partially reverse hypertension and cardiovascular damage.8

In 2011, Choi et al identified 2 somatic mutations (G151R, L168R) in the KCNJ5 gene (encoding a potassium inwardly rectifying channel) in 8 out of 22 sporadic APAs.9 The authors explained that KCNJ5 mutations resulted in a loss of K+ channel selectivity and constitutive aldosterone production. This discovery has provided new insight into the molecular mechanisms of APA pathogenesis. More recently, somatic mutations in 3 other genes, namely, ATP1A1 (encoding the α1 subunit of the Na+/K+-ATPase), ATP2B3 (encoding the plasma membrane Ca2+-ATPase 3), and CACNA1D (encoding the CaV1.3 channel), were revealed to increase aldosterone biosynthesis in APAs.10–12 Mutations of these genes could affect adrenal zona glomerulosa cell membrane potential and intracellular ionic homeostasis.

As these acquired mutations were only detected in resected APAs, the clinical implications of somatic mutations remain to be determined. Intriguingly, recent observations showed that KCNJ5 mutation carriers might exhibit a more florid phenotype with younger age,13,14 higher aldosterone level,13,14 and prominent cardiac damage.15 Currently, there has not been agreement on the correlation between KCNJ5 mutations and response to adrenalectomy.15,16 Therefore, a greater number of cases need to be studied to evaluate the clinical characteristics of patients with and without somatic mutations in APAs. There has been no study investigating somatic mutations in APAs in China thus far.

In this study, we explored KCNJ5, ATP1A1, ATP2B3, and CACNA1D for mutations in 168 consecutive Chinese patients with sporadic APA and investigated the clinical and biochemical characteristics associated with somatic mutations.

Methods

An expanded Methods section is available in the online-only Data Supplement.

Subjects and Diagnostic Criteria

One hundred sixty-eight cases with APA (83 males and 85 females) were consecutively enrolled in the study from 2008 to 2014. All cases were hospitalized in the Department of Hypertension for diagnosis and then underwent adrenalectomy in the Department of Urology (Ruijin Hospital, Shanghai Jiao Tong University School of Medicine). The diagnostic process of APA was formulated accordingly based on the recommendations of current guidelines (Figure S1 in the online-only Data Supplement).6,17 All subjects provided written informed consent, and the procedure got approval of the local ethics committee. The detailed procedure is shown in the online-only Data Supplement.

Sequencing of the KCNJ5, ATP1A1, ATP2B3, and CACNA1D Genes

Detailed data for DNA extraction and Sanger Sequencing are available in the online-only Data Supplement.

Western Blotting

Western blotting was performed to detect KCNJ5 protein expression in 50 APAs. Relative protein quantification was evaluated by Image J 1.44 (National Institutes of Health, Bethesda, MD).

Biophysical Properties of the KCNJ5T148-T149insR Mutation in Vitro

Adrenocortical carcinoma NCI-H295R cells or human embryonic kidney 293T cells were transiently transfected with KCNJ5T148-T149insR (or KCNJ5WT as control) and KCNJ3. The mRNA expression of CYP11B2 (aldosterone synthase gene) was assessed, and the supernatant was collected for aldosterone measurement. In addition, whole-cell voltage clamp recordings were performed.

Statistical Analysis

Statistical analyses were performed using the SPSS Statistics 19.0. Categorical variables were compared with chi-square test. Normally distributed continuous variables were presented as mean±SD and analyzed using Student’s t test or 1-way ANOVA. Skewed variables were presented as median (25th–75th percentile), which underwent logarithmic or square transformation before Student’s t test. If not appropriate, skewed variables were analyzed using Mann–Whitney U test. P<0.05 was considered as statistically significant.

Results

KCNJ5 Sequencing and Identification of a New KCNJ5 Mutation

Somatic KCNJ5 mutations were screened in 129 (76.8%) of the 168 APAs (Table 1). In these 129 cases, no KCNJ5 mutation was found in the normal adrenal tissue (n=116) or peripheral blood (n=87). The KCNJ5 mutations included G151R, L168R, and T158A mutations in 67, 60, and 1 case(s), respectively, and a novel insertion mutation (c.445-446insGAA, p.T148-T149insR) in a patient (Figure 1A). Of the 67 cases with recurrent G151R, 41 carried c.451G>A, and the remaining 26 carried c.451G>C. In addition, homology alignments of the protein sequences showed that all 4 identified mutations are highly conserved among most species (Figure S2A).

View this table:
Table 1.

Prevalence of Somatic KCNJ5 Mutations in Aldosterone-Producing Adenomas in Various Study Populations

Figure 1.
Figure 1.

Typical sequences of specific mutations in the KCNJ5, ATP1A1, and ATP2B3 genes in aldosterone-producing adenomas (APAs). No mutation was found in normal adjacent adrenal gland tissue (AAG) or peripheral blood. A, T148-T149insR in KCNJ5. B, M102-L103del in ATP1A1. C, delV422-V426insSTL in ATP2B3.

No somatic mutation was found in the KCNJ5 gene in 11 cortisol-producing adenomas, 10 adrenal pheochromocytomas, or 26 nonfunctional adrenal adenomas.

Sequencing of the ATP1A1, ATP2B3, and CACNA1D Genes

In the 39 cases without KCNJ5 mutations, 6 cases were found with somatic mutations in ATP1A1 (n=4, male), ATP2B3 (n=1, male), or CACNA1D (n=1, female; Table 2). These included a known ATP1A1 mutation (L104R, 3 cases) and a known CACNA1D mutation (G403R, 1 case), as well as a new ATP1A1 variant (c.304-309delATGTTA, p.M102-L103del; Figure 1B) and a new ATP2B3 variant (c.1264-1278delGTCACTGTGCTGGTCinsAGCACACTC, p.delV422-V426insSTL; Figure 1C). Of these, the ATP1A1 variants and the ATP2B3 variant were highly conserved in most species (Figures S2B and S2C). None of these mutations were found in the normal adjacent adrenal tissue (n=6) and peripheral blood (n=3).

View this table:
Table 2.

Prevalence of Somatic ATP1A1, ATP2B3, and CACNA1D Mutations in Aldosterone-Producing Adenomas in Various Study Populations

Phenotypic Characteristics of Patients With and Without Somatic KCNJ5 Mutations

Carriers and noncarriers of the KCNJ5 mutations were similar in age at operation, duration of hypertension, baseline systolic blood pressure, diastolic blood pressure, plasma aldosterone concentration, urinary protein excretion, glomerular filtration rate, and left ventricle mass index (P≥0.075; Table 3). Nonetheless, carriers of the somatic KCNJ5 mutations, compared with noncarriers, had a higher proportion of women (56.6% versus 33.3%; P=0.02), larger tumor size (P=0.02), higher urinary aldosterone excretion (P=0.038), and aldosterone–renin ratio (P=0.007), greater lateralization index (P=0.052), and lower plasma renin activity (P=0.018), and minimal serum K+ level (P=0.022). After adjustment for sex and age, all differences remained significant (P≤0.053; Table 3).

View this table:
Table 3.

Clinical and Biochemical Characteristics of Aldosterone-Producing Adenomas With and Without KCNJ5 Mutations

The patient harboring the novel KCNJ5T148-T149insR mutation was a 62-year-old female and had hypertension for >20 years. Systolic/diastolic blood pressures were 160/90 mm Hg under 3 antihypertensive drugs. The minimal serum K+ concentration was 2.1 mmol/L and aldosterone–renin ratio was 95 (ng/dL)/(ng/mL/h). A right adrenal mass (20 mm in diameter) showed aldosterone hypersecretion (lateralization index=5.6).

KCNJ5 Protein Expression in APAs

We performed western blotting in 31 APAs with KCNJ5 mutations and 19 APAs without the KCNJ5 mutations to investigate whether mutant KCNJ5 was associated with altered expression of KCNJ5 protein. We did not find significant change of the KCNJ5 protein expression in APAs with mutant KCNJ5 (P=0.207; Figure 2).

Figure 2.
Figure 2.

Effect of KCNJ5 mutations on KCNJ5 protein expression in aldosterone-producing adenomas (APAs). KCNJ5 protein expression in APAs carrying wild-type KCNJ5 (n=19) and mutant KCNJ5 (n=31) was evaluated by western blotting. Data were presented as median (25th–75th percentile) and analyzed using Mann–Whitney U test.

Biophysical Properties of the KCNJ5T148-T149insR Mutation in Vitro

We investigated the effect of the insertion mutation T148-T149insR in KCNJ5 on aldosterone expression by transiently cotransfecting KCNJ3 with mutant or wild-type KCNJ5 in H295R cells. At 48 hours after electroporation, T148-T149insR, compared with wild type and empty vector, could stimulate CYP11B2 mRNA upregulation by 9.8-fold (P<0.001) and 7.2-fold (P<0.001; Figure 3A), respectively. After adjustment for total protein, H295R cells expressing T148-T149insR released more aldosterone to the supernatant, 5.4-fold (P<0.001) and 5.0-fold (P<0.001) higher than cells expressing wild-type and empty vector (Figure 3B), respectively.

Figure 3.
Figure 3.

Aldosterone production from NCI-H295R cells transiently electroporated with KCNJ3 and wild-type or mutant KCNJ5 (T148-T149insR). At 48 h after transfection, the samples were collected and analyzed. A, CYP11B2 mRNA levels.B, Aldosterone concentration being adjusted for total protein. Data were presented as mean±SD and assessed by 1-way analysis of variance followed by post hoc analysis. *P<0.001. n=5 for each group.

We further explored the underlying mechanism for the T148-T149insR mutation causing increased aldosterone production. We coexpressed KCNJ3 with mutant or wild-type KCNJ5 in 293T cells and recorded currents at voltages ranging from −100 mV to +60 mV by whole-cell recordings with physiological solutions and extracellular Na+ free solutions (Figure 4). KCNJ3/KCNJ5WT induced an inwardly rectifying current with a reversal potential of −23±3 mV. This current was remarkably decreased in the presence of BaCl2 by 90.4% at −100 mV, which was used to test the K+ channel sensitivity to barium. In contrast, KCNJ3/KCNJ5T148-T149insR produced a current which was only partially blocked in the presence of BaCl2 by 28.3% at −100 mV. In addition, this mutant channel exhibited membrane depolarization with a less negative reversal potential (−3±1 mV). The substitution of choline for extracelluar Na+ markedly inhibited the currents of the mutant channel with a hyperpolarized potential (−23±2 mV).

Figure 4.
Figure 4.

Whole-cell current from 293T cells transiently cotransfected with KCNJ3 and wild-type or mutant KCNJ5 (T148-T149insR). At 24 h after transfection, whole-cell voltage clamp recordings were performed on cotransfected cells in response to voltage-clamp pulses from −100 mV to +60 mV in 20 mV steps in the presence of extracellular Na+ (control) and after extracellular Na+ replacement by choline chloride (Na+ free). 1 mmol/L BaCl2 was added. A, Representative traces of currents. B, Current–voltage relationships. C, Reverse potentials. Data were presented as mean±SD and analyzed using Student’s t test. *P<0.01, wild-type versus T148-T149insR. †P<0.001, control versus Na+ free. n=6 to 8.

We also studied the effect of KCNJ5T148-T149insR on intracellular Ca2+ homeostasis in cotransfected H295R cells with KCNJ3 and mutant KCNJ5 or wild-type KCNJ5. The intracellular Ca2+ concentration as assessed by the Fura-2/AM ratio was higher in KCNJ3/KCNJ5T148-T149insR cells than in KCNJ3/KCNJ5WT and empty vector cells both by 1.2-fold (P<0.01; Figure S3).

Discussion

Our study is the first to report somatic mutations in the KCNJ5 gene and several other genes in Chinese patients with APA. Indeed, 76.8% of the Chinese APAs had somatic KCNJ5 mutations, and in the absence of the KCNJ5 mutations, some, though not many, had somatic mutations in the ATP1A1, ATP2B3, and CACNA1D genes. Our observation on the remarkably high proportion of KCNJ5 mutations is in line with the result of a Japanese study where the prevalence was 65.2% in 23 Japanese APAs.14 In a review study across populations, the total prevalence of somatic KCNJ5 mutations in APAs was ≈40%.7

Our observations on the characteristics of patients with somatic KCNJ5 mutations are also in accordance with the results of several other studies in different populations in several aspects.10,13,14,18–22 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. The patients with KCNJ5 mutations were more likely to be diagnosed and receive adrenalectomy. Third, in the presence of KCNJ5 mutations, the minimal K+ concentration was lower. Because severe hypokalemia was a major indicator of PA, the patients with KCNJ5 mutations were therefore more likely to be screened for PA. These characteristics of patients with KCNJ5 mutations suggest that identification of the mutations may have prognostic significance.

In our study, the KCNJ5 mutations did not affect the expression of the protein. This finding is in agreement with the result of a previous report.20 We further investigated the function of the novel somatic KCNJ5 mutation (T148-T149insR). Our findings indicate that this mutation is capable of increasing aldosterone production, as several previously identified mutations (W126R,23 G151R,23 T158A,24 and Ins T14925). The patient harboring this mutation was also resistant to drug treatment as described in another report.25 Of note, using the active heterotetramers of KCNJ3/KCNJ5,26 we observed that CYP11B2 mRNA expression was upregulated by 9.8-fold and aldosterone concentration by 5.4-fold in KCNJ3/KCNJ5T148-T149insR expressing cells, compared with KCNJ3/KCNJ5wild type. We therefore conclude that this mutation may also stimulate aldosterone biosynthesis.

The underlying mechanisms for the relationship between T148-T149insR in KCNJ5 and aldosterone biosynthesis remain incompletely understood. This novel mutation is positioned closely to the K+ channel selectivity filter and is highly conserved among disparate species. It is clear that the T148-T149insR mutation caused a loss of K+ ion selectivity and a less negative reversal potential, which might be accompanied with a pathological Na+ permeability similarly as the mutations at G151.9,27,28 Other somatic mutations (G151R,9 L168R,9 del I157,29 and Ins T14925) in KCNJ5 also had the similar electrophysiological feature. Membrane depolarization in the adrenal zona glomerulosa cells could increase intracellular Ca2+ concentration through activation of voltage-gated Ca2+ channels and Na+/Ca2+ exchangers, which led to aldosterone biosynthesis eventually.25

Our finding on the mutations of ATP1A1 and ATP2B3 is also consistent with the results of a recent study in 2 aspects.10 First, KCNJ5 and ATP1A1 or ATP2B3 mutations were not concomitantly observed. Second, ATPase alterations showed male dominance.

Limitations

This work was conducted in a single center and not representative of the whole APAs. 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.

In summary, we investigated the prevalence of KCNJ5, ATP1A1, ATP2B3, and CACNA1D mutations in the Chinese patients with sporadic APA. Patients with the KCNJ5 mutations had clearly distinguishable phenotypes. The T148-T149insR mutation in KCNJ5 might influence K+ channel selectivity and autonomous aldosterone production.

Perspectives

The trigger for the occurrence of somatic mutations in APAs would be an interesting research theme. As there is currently no definite correlation between somatic KCNJ5 mutations and nodule formation,31 further investigation on this aspect is needed. In addition, easily accessible biomarkers of APAs should be explored in other possible biological samples.

Acknowledgments

We thank Chenlong Chu and Chenhui Zhao (Department of Urology, Luwan Branch of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China) for helpful support on the storage of tissues. We also thank Kaida Ji and Ying Zhang (Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China) for technical assistance on DNA isolation.

Sources of Funding

This study was supported by grants from National High Technology Research and Development Program 863 of China (2012AA02A516), grants from the State Key Program of the National Natural Science foundation of China (81230071), and grants from Shanghai Municipal Science and Technology Commission public service platform (12DZ2295200).

Disclosures

None.

Footnotes

  • Received September 2, 2014.
  • Revision received September 15, 2014.
  • Accepted December 20, 2014.

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Novelty and Significance

What Is New?

  • The prevalence of KCNJ5 mutations in our Chinese subjects with aldosterone-producing adenoma was 76.8%. Mutations in ATP1A1, ATP2B3, and CACNA1D were rare.

  • We found a novel insertion mutation (c.445-446insGAA, p.T148-T149insR) in KCNJ5 in a female patient and a novel mutation in ATP1A1 and ATP2B3, respectively.

What Is Relevant?

  • KCNJ5 mutations were more prevalent in females, whereas ATPase mutations were males.

  • KCNJ5 mutation carriers had larger adenomas, higher aldosterone production, and lower minimal serum K+ level.

  • T148-T149insR in KCNJ5 might influence membrane voltage and Ca2+ homeostasis and increase CYP11B2 mRNA expression and aldosterone production.

Summary

Somatic KCNJ5 mutations have a distinctively high prevalence in sporadic aldosterone-producing adenomas in Chinese compared with ATP1A1, ATP2B3, and CACNA1D mutations. Patients with KCNJ5 mutations had distinguishable phenotypes. T148-T149insR in KCNJ5 might participate in the loss of K+ channel selectivity and increase aldosterone synthesis.

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  • Clinical Characteristics of Somatic Mutations in Chinese Patients With Aldosterone-Producing AdenomaNovelty and Significance
    Fang-Fang Zheng, Li-Min Zhu, Ai-Fang Nie, Xiao-Ying Li, Jing-Rong Lin, Ke Zhang, Jing Chen, Wen-Long Zhou, Zhou-Jun Shen, Yi-Chun Zhu, Ji-Guang Wang, Ding-Liang Zhu and Ping-Jin Gao
    Hypertension. 2015;65:622-628, originally published January 26, 2015
    https://doi.org/10.1161/HYPERTENSIONAHA.114.03346
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