Publication Date:
2011-02-12
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371087/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371087/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Choi, Murim -- Scholl, Ute I -- Yue, Peng -- Bjorklund, Peyman -- Zhao, Bixiao -- Nelson-Williams, Carol -- Ji, Weizhen -- Cho, Yoonsang -- Patel, Aniruddh -- Men, Clara J -- Lolis, Elias -- Wisgerhof, Max V -- Geller, David S -- Mane, Shrikant -- Hellman, Per -- Westin, Gunnar -- Akerstrom, Goran -- Wang, Wenhui -- Carling, Tobias -- Lifton, Richard P -- DK54983/DK/NIDDK NIH HHS/ -- K01 AR060300/AR/NIAMS NIH HHS/ -- T32 GM007205/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 Feb 11;331(6018):768-72. doi: 10.1126/science.1198785.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21311022" target="_blank"〉PubMed〈/a〉
Keywords:
Adrenal Cortex Neoplasms/*genetics/metabolism/pathology
;
Adrenal Glands/pathology
;
Adrenocortical Adenoma/*genetics/metabolism/pathology
;
Aldosterone/*metabolism
;
Cell Line
;
Cell Proliferation
;
Female
;
G Protein-Coupled Inwardly-Rectifying Potassium
;
Channels/chemistry/*genetics/metabolism
;
Humans
;
Hyperaldosteronism/*genetics/metabolism/pathology
;
Hyperplasia
;
Hypertension/*genetics/metabolism
;
Male
;
Mutant Proteins/chemistry/genetics/metabolism
;
*Mutation
;
Potassium/metabolism
;
Protein Multimerization
;
Sodium/metabolism
;
Zona Glomerulosa/metabolism/pathology
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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