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      Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism

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          Abstract

          Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel KCNJ5 that result in cell depolarization and Ca 2+ influx cause ~40% of these tumors 1 . We found five somatic mutations (four altering glycine 403, one altering isoleucine 770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 non- KCNJ5-mutant APAs. These mutations lie in S6 segments that line the channel pore. Both result in channel activation at less depolarized potentials, and glycine 403 mutations also impair channel inactivation. These effects are inferred to cause increased Ca 2+ influx, the sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa 2 . Remarkably, we identified de novo mutations at the identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain of function Ca 2+ channel mutations in aldosterone-producing adenomas and primary aldosteronism.

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          Most cited references24

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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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            Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.

            We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.
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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

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                3 July 2013
                04 August 2013
                September 2013
                01 March 2014
                : 45
                : 9
                : 1050-1054
                Affiliations
                [1 ]Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
                [2 ]Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA
                [3 ]Institute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum Jülich, 52425 Jülich, Germany
                [4 ]Institut für Neurophysiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany
                [5 ]Yale Center for Mendelian Genomics, New Haven, CT 06510, USA
                [6 ]Department of Surgery, Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, CT 06510, USA
                [7 ]Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
                [8 ]Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA
                [9 ]Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
                [10 ]Nemours Children’s Clinic, Jacksonville, Florida 32207, USA
                [11 ]Johns Hopkins Pediatric Nephrology, Baltimore, MD 21287, USA
                [12 ]Osteogenesis Imperfecta Program, Kennedy Krieger Institute, Baltimore, MD 21205, USA
                [13 ]Department of Surgery, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY 10467, USA
                [14 ]Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA
                Author notes
                Correspondence to: Richard P. Lifton, M.D., Ph.D., Departments of Genetics and Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, 333 Cedar St., SHM I308, New Haven, CT 06510, USA. Telephone: +1-203-737-4420, Fax: +1-203-785-7560, richard.lifton@ 123456yale.edu
                [15]

                These authors contributed equally to this work.

                Article
                NIHMS491411
                10.1038/ng.2695
                3876926
                23913001
                16a1043d-e611-474b-a22f-8618cdad39dd

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                Genetics
                Genetics

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