K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.

Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
Science (Impact Factor: 31.48). 02/2011; 331(6018):768-72. DOI: 10.1126/science.1198785
Source: PubMed

ABSTRACT 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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    ABSTRACT: AIM: Increased serum levels of insulin growth factor (IGF) and insulin have been reported in patients with chronic hepatitis C. Insulin and IGF-1 have also been associated with increased growth of adrenal cells in culture. These observations suggest that both IGF and insulin can trigger adrenal tumorigenesis. Adrenal tumors have been reported in a series of patients with chronic hepatitis C; accordingly, the aim of this study was to explore further this potential association. METHODS: Patients with a diagnosis of adrenal tumors over the past ten years were identified and their records reviewed for evidence of chronic hepatitis C. The control group was comprised of age-matched subjects who had had a CT or MRI of the abdomen during the same study period, and had documentation of hepatitis C status. RESULTS: Twenty three patients with adrenal tumors were identified. Fifteen of these patients (65.2%) had hepatitis C antibody in serum; eleven (47.8%) of these had hepatitis C RNA, confirming chronic hepatitis C (CHC). In the control group, in contrast, only one of twenty-three patients (4.3%) had hepatitis C antibody in serum, which was significantly lower than in the study group (p value<0.0005). CONCLUSION: There is an association between chronic hepatitis C and adrenal tumors. Adrenal tumors may be one of the extrahepatic manifestations of this viral infection. The recognition of this association by clinicians will dramatically change the approach to patients with chronic hepatitis C and manifestations, even subtle, of functional adrenal tumors, which require diagnostic evaluation and treatment.
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    eLife Sciences 04/2015; 4. DOI:10.7554/eLife.06315 · 8.52 Impact Factor
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    The Journal of Clinical Endocrinology and Metabolism 04/2015; DOI:10.1210/jc.2015-1734 · 6.31 Impact Factor

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