Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas (original) (raw)
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Somatic ATP1A1 , ATP2B3 , and KCNJ5 Mutations in Aldosterone-Producing Adenomas
Hypertension, 2013
Aldosterone-producing adenomas (APAs) cause a sporadic form of primary aldosteronism and somatic mutations in the KCNJ5 gene, which encodes the G-protein–activated inward rectifier K + channel 4, GIRK4, account for ≈40% of APAs. Additional somatic APA mutations were identified recently in 2 other genes, ATP1A1 and ATP2B3 , encoding Na + /K + -ATPase 1 and Ca 2+ -ATPase 3, respectively, at a combined prevalence of 6.8%. We have screened 112 APAs for mutations in known hotspots for genetic alterations associated with primary aldosteronism. Somatic mutations in ATP1A1 , ATP2B3 , and KCNJ5 were present in 6.3%, 0.9%, and 39.3% of APAs, respectively, and included 2 novel mutations (Na + /K + -ATPase p.Gly99Arg and GIRK4 p.Trp126Arg). CYP11B2 gene expression was higher in APAs harboring ATP1A1 and ATP2B3 mutations compared with those without these or KCNJ5 mutations. Overexpression of Na + /K + -ATPase p.Gly99Arg and GIRK4 p.Trp126Arg in HAC15 adrenal cells resulted in upregulation of CYP...
Scientific Reports, 2015
Primary aldosteronism (PA) is a common form of secondary hypertension and has significant cardiovascular consequences. Mutated channelopathy due to the activation of calcium channels has been recently described in aldosterone-producing adenoma (APA). The study involved 148 consecutive PA patients, (66 males; aged 56.3 ± 12.3years) who received adrenalectomy, and were collected from the Taiwan PA investigator (TAIPAI) group. A high rate of somatic mutation in APA was found (n = 91, 61.5%); including mutations in KCNJ5 (n = 88, 59.5%), ATP1A1 (n = 2, 1.4%), and ATP2B3 (n = 1, 0.7%); however, no mutations in CACNA1D were identified. Mutation-carriers were younger (<0.001), had lower Cyst C (p = 0.042), pulse wave velocity (p = 0.027), C-reactive protein (p = 0.042) and a lower rate of proteinuria (p = 0.031) than non-carriers. After multivariate adjustment, mutation carriers had lower serum CRP levels than non-carriers (p = 0.031. Patients with mutation also had a greater chance of recovery from hypertension after operation (p = 0.005). A high incidence of somatic mutations in APA was identified in the Taiwanese population. Mutationcarriers had lower CRP levels and a higher rate of cure of hypertension after adrenalectomy. This raises the possibility of using mutation screening as a tool in predicting long-term outcome after adrenalectomy.
Hypertension (Dallas, Tex. : 1979), 2017
Mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 are thought to cause the excessive autonomous aldosterone secretion of aldosterone-producing adenomas (APAs). The histopathology of KCNJ5 mutant APAs, the most common and largest, has been thoroughly investigated and shown to have a zona fasciculata-like composition. This study aims to characterize the histopathologic spectrum of the other genotypes and document the proliferation rate of the different sized APAs. Adrenals from 39 primary aldosteronism patients were immunohistochemically stained for CYP11B2 to confirm diagnosis of an APA. Twenty-eight adenomas had sufficient material for further analysis and were target sequenced at hot spots in the 5 causal genes. Ten adenomas had a KCNJ5 mutation (35.7%), 7 adenomas had an ATP1A1 mutation (25%), and 4 adenomas had a CACNA1D mutation (14.3%). One novel mutation in exon 28 of CACNA1D (V1153G) was identified. The mutation caused a hyperpolarizing shift of the voltage-dependent ac...
Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma
2014
A rterial hypertension is a major cardiovascular risk factor that affects 10% to 40% of the adult population in industrialized countries. Detection of secondary forms of hypertension is particularly important because it allows the targeted management of the underlying disease. Primary aldosteronism (PA) is the most common form of secondary hypertension with an estimated prevalence of ≈10% in referred patients and 4% in primary care but as high as 20% in patients with resistant hypertension. 1-5 PA is caused by the excessive production of aldosterone from the adrenal cortex, resulting in hypertension associated with high plasma aldosterone levels, low plasma renin activity, and varying degrees of hypokalemia and metabolic alkalosis. Long-term consequences include an increased risk of myocardial infarction, stroke, and atrial fibrillation. 6,7
The Journal of Clinical Endocrinology & Metabolism, 2016
Context: Recurrent somatic mutations in KCNJ5, CACNA1D, ATP1A1, and ATP2B3 have been identified in aldosterone-producing adenomas (APAs). The question as to whether they are responsible for both nodulation and aldosterone production is not solved. Case Description: We describe the case of a young patient who was diagnosed with severe arterial hypertension due to primary aldosteronism at age 26 years, followed by hemorrhagic stroke 4 years later. Abdominal computed tomography showed bilateral macronodular adrenal hyperplasia. Identification of lateralized aldosterone secretion led to right adrenalectomy, followed by normalization of biochemical and hormonal parameters and amelioration of blood pressure. The resected adrenal showed three nodules, one of them expressing aldosterone synthase and harboring a somatic KNCJ5 mutation. A Weiss revisited index of 3 of the APA prompted us to perform a second 18F-2-fluoro-2-deoxy-D-glucose-positron emission tomography after surgery, which revea...
Genetics of Aldosterone-Producing Adenoma in Korean Patients
PloS one, 2016
Recently, somatic mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D genes were found to be associated with the pathogenesis of aldosterone-producing adenoma (APA). This study aimed to investigate the prevalence of somatic mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D and examine the correlations between these mutations and the clinical and biochemical characteristics in Korean patients with APA. We performed targeted gene sequencing in 66 patients with APA to detect somatic mutations in these genes. Somatic KCNJ5 mutations were found in 47 (71.2%) of the 66 patients with APA (31 cases of p.G151R and 16 cases of p.L168R); these two mutations were mutually exclusive. Somatic mutations in the ATP1A1, ATP2B3, and CACNA1D genes were not observed. Somatic KCNJ5 mutations were more prevalent in female patients (66% versus 36.8%, respectively; P = 0.030). Moreover, patients with KCNJ5 mutations comprised a significantly higher proportion of patients younger than 35 years of age (19.1% versu...
Prevalence, Clinical, and Molecular Correlates of KCNJ5 Mutations in Primary Aldosteronism
Hypertension, 2012
Primary aldosteronism is the most common form of secondary hypertension. Mutations in the KCNJ5 gene have been described recently in aldosterone-producing adenomas (APAs). The aim of this study was to investigate the prevalence of KCNJ5 mutations in unselected patients with primary aldosteronism and their clinical, biological and molecular correlates. KCNJ5 sequencing was performed on somatic (APA, n=380) and peripheral (APA, n=344; bilateral adrenal hyperplasia, n=174) DNA of patients with primary aldosteronism, collected through the European Network for the Study of Adrenal Tumors. Transcriptome analysis was performed in 102 tumors. Somatic KCNJ5 mutations (p.Gly151Arg or p.Leu168Arg) were found in 34% (129 of 380) of APA. They were significantly more prevalent in females (49%) than males (19%; P <10 −3 ) and in younger patients (42.1±1.0 versus 47.6±0.7 years; P <10 −3 ) and were associated with higher preoperative aldosterone levels (455±26 versus 376±17 ng/L; P =0.012) bu...
F1000 - Post-publication peer review of the biomedical literature, 2000
Endocrine tumors such as aldosterone-producing adrenal adenomas (APAs), a cause of severe hypertension, feature constitutive hormone production and unrestrained cell proliferation; the mechanisms linking these events are unknown. We identify two recurrent somatic mutations in and near the selectivity filter of the potassium (K +) channel KCNJ5 that are present in 8 of 22 human APAs studied. Both produce increased sodium (Na +) conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium (Ca 2+) entry, the signal for aldosterone production and cell proliferation. Similarly, we identify an inherited KCNJ5 mutation that produces increased Na + conductance in a Mendelian form of severe aldosteronism and massive bilateral adrenal hyperplasia. These findings explain pathogenesis in a subset of patients with severe hypertension and implicate loss of K + channel selectivity in constitutive cell proliferation and hormone production. Aldosterone, a steroid hormone synthesized by the adrenal glomerulosa, is normally produced in two conditions, intravascular volume depletion and hyperkalemia (high plasma
PLoS ONE, 2012
Background: Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na + conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.