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      Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter

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      1 , 1 , 1 , 1 , 2 , 3 , 7 , 3 , 7 , 6 , 1 , 11 , 22 , 8 , 12 , 13 , 14 , 20 , 21 , 15 , 11 , 5 , 5 , 6 , 18 , 9 , 1 , 19 , 4 , 1 , 11 , 1 , 18 , 12 , 1 , 2 , 10 , 10 , 1 , *
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          Abstract

          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.

          Materials and Methods

          The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers.

          Results

          G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions.

          KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005).

          Discussion

          Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.

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          Most cited references19

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          A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients.

          We prospectively investigated the prevalence of curable forms of primary aldosteronism (PA) in newly diagnosed hypertensive patients. The prevalence of curable forms of PA is currently unknown, although retrospective data suggest that it is not as low as commonly perceived. Consecutive hypertensive patients referred to 14 hypertension centers underwent a diagnostic protocol composed of measurement of Na+ and K+ in serum and 24-h urine, sitting plasma renin activity, and aldosterone at baseline and after 50 mg captopril. The patients with an aldosterone/renin ratio >40 at baseline, and/or >30 after captopril, and/or a probability of PA (by a logistic discriminant function) > or =50% underwent imaging tests and adrenal vein sampling (AVS) or adrenocortical scintigraphy to identify the underlying adrenal pathology. An aldosterone-producing adenoma (APA) was diagnosed in patients who in addition to excess autonomous aldosterone secretion showed: 1) lateralized aldosterone secretion at AVS or adrenocortical scintigraphy, 2) adenoma at surgery and pathology, and 3) a blood pressure decrease after adrenalectomy. Evidence of excess autonomous aldosterone secretion without such criteria led to a diagnosis of idiopathic hyperaldosteronism (IHA). A total of 1,180 patients (age 46 +/- 12 years) were enrolled; a conclusive diagnosis was attained in 1,125 (95.3%). Of these, 54 (4.8%) had an APA and 72 (6.4%) had an IHA. There were more APA (62.5%) and fewer IHA cases (37.5%) at centers where AVS was available (p = 0.002); the opposite occurred where AVS was unavailable. In newly diagnosed hypertensive patients referred to hypertension centers, the prevalence of APA is high (4.8%). The availability of AVS is essential for an accurate identification of the adrenocortical pathologies underlying PA.
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            Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline.

            Our objective was to develop clinical practice guidelines for the diagnosis and treatment of patients with primary aldosteronism. The Task Force comprised a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, six additional experts, one methodologist, and a medical writer. The Task Force received no corporate funding or remuneration. Systematic reviews of available evidence were used to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group criteria to describe both the quality of evidence and the strength of recommendations. We used "recommend" for strong recommendations and "suggest" for weak recommendations. Consensus was guided by systematic reviews of evidence and discussions during one group meeting, several conference calls, and multiple e-mail communications. The drafts prepared by the task force with the help of a medical writer were reviewed successively by The Endocrine Society's CGS, Clinical Affairs Core Committee (CACC), and Council. The version approved by the CGS and CACC was placed on The Endocrine Society's Web site for comments by members. At each stage of review, the Task Force received written comments and incorporated needed changes. We recommend case detection of primary aldosteronism be sought in higher risk groups of hypertensive patients and those with hypokalemia by determining the aldosterone-renin ratio under standard conditions and that the condition be confirmed/excluded by one of four commonly used confirmatory tests. We recommend that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma. We recommend the presence of a unilateral form of primary aldosteronism should be established/excluded by bilateral adrenal venous sampling by an experienced radiologist and, where present, optimally treated by laparoscopic adrenalectomy. We recommend that patients with bilateral adrenal hyperplasia, or those unsuitable for surgery, optimally be treated medically by mineralocorticoid receptor antagonists.
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              K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.

              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.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                27 July 2012
                : 7
                : 7
                : e41926
                Affiliations
                [1 ]Department of Surgical Sciences, Genetics and Pathology, Uppsala University, Uppsala, Sweden
                [2 ]Department of Surgery, School of Medicine, Yale University, New Haven, Connecticut, United States of America
                [3 ]Department of General, Visceral and Pediatric Surgery, University Hospital Düsseldorf, Düsseldorf, Germany
                [4 ]Department of General, Visceral and Vascular Surgery, University Hospital, University of Halle-Wittenberg, Halle/Saale, Germany
                [5 ]Department of Molecular Medicine and Surgery, Endocrine Surgery Unit, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
                [6 ]Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
                [7 ]Department of Endocrinology, Diabetes and Rheumatology, University Hospital Düsseldorf, Düsseldorf, Germany
                [8 ]Institute of Pathology, University Hospital Düsseldorf, Düsseldorf, Germany
                [9 ]Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
                [10 ]Department of Genetics, School of Medicine, Yale University, New Haven, Connecticut, United States of America
                [11 ]University of Sydney, Endocrine Surgical Unit and Cancer Genetics, Hormones and Cancer Group , Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia
                [12 ]Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Kliniken Essen-Mitte, Universität Duisburg-Essen, Essen, Germany
                [13 ]Institut für Pathologie und Neuropathologie Universitätsklinikum, Universität Duisburg-Essen, Essen, Germany
                [14 ]Department of Pathology, Centre Hospitalier Lyon Sud, Lyon, France
                [15 ]Department of Endocrine Surgery, Centre Hospitalier Lyon Sud, Lyon, France
                [16 ]Department of Pathology, University Hospital Lübeck, Lübeck, Germany
                [17 ]Department of Pathology, Marienhospital, Hamburg, Germany
                [18 ]Medizinischen Klinik Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
                [19 ]Endocrine Surgery, Centre Hospitalier Poitiers, Poitiers, France
                [20 ]Pathology Department, Centre Hospitalier Poitiers, Poitiers, France
                [21 ]Sahlgrenska akademin, Göteborg University, Göteborg, Sweden
                [22 ]Department of Surgery, Bankstown Hospital, South Western Sydney Clinical School, University of New South Wales, Sydney, Australia
                The Chinese University of Hong Kong, Hong Kong
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: PB. Performed the experiments: PB TÅ JC ADV LFS. Analyzed the data: PB TÅ JC ADV GÅ RPL GW. Contributed reagents/materials/analysis tools: KC HSW WTK WS AF JI PS MA PFA KWS MD PL BW JLP BR JZ MB SC KAI JB PS JLK HD PH SS GW HL MKW GÅ TC MC RPL PB. Wrote the paper: TÅ GÅ GW HSW BR MKW PB.

                Article
                PONE-D-11-08927
                10.1371/journal.pone.0041926
                3407065
                22848660
                8c94b1a0-07b2-4ffa-8304-eb5753564551
                Copyright @ 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 21 February 2012
                : 29 June 2012
                Page count
                Pages: 7
                Funding
                This work was supported by grants from Swedish Cancer Society to P Björklund and G Åkerström, the Swedish Research Council to G Westin, Swedish Society for Medical Research, Åke Wiberg Foundation, Selander Foundation and Jeanssons Foundation to P Björklund and the Leducq Transatlantic Network for Hypertension to R Lifton. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Computational Biology
                Population Genetics
                Mutation
                Medicine
                Clinical Genetics
                Genetic Testing
                Endocrinology
                Adrenal Cortex
                Neuroendocrinology
                Oncology
                Basic Cancer Research
                Surgery
                Endocrine Surgery
                Surgical Oncology

                Uncategorized
                Uncategorized

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