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10.1210/jc.2014-1927 http://scihub22266oqcxt.onion/10.1210/jc.2014-1927 C4154085!4154085 !25057880     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=25057880 &cmd=llinks): Failed to open stream: HTTP request failed! 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A novel KCNJ5-insT149 somatic mutation close to, but outside, the selectivity filter causes resistant hypertension by loss of selectivity for potassium |pdf=|usr=}}{{25057880 }} gab.com Text A novel KCNJ5-insT149 somatic mutation close to, but outside, the selectivity filter causes resistant hypertension by loss of selectivity for potassium JO: J Clin Endocrinol Metab http://www.kidney.de/pget.php?&tw=1&pmid=25057880 #FOAvip CONTEXT: Understanding the function of the KCNJ5 potassium channel through characterization of naturally occurring novel mutations is key for dissecting the mechanism(s) of autonomous aldosterone secretion in primary aldosteronism. OBJECTIVE: We sought for such novel KCNJ5 channel mutations in a large database of patients with aldosterone-producing adenomas (APAs). METHODS: We discovered a novel somatic c.446insAAC insertion, resulting in the mutant protein KCNJ5-insT149, in a patient with severe drug-resistant hypertension among 195 consecutive patients with a conclusive diagnosis of APA, 24.6% of whom showed somatic KCNJ5 mutations. By site-directed mutagenesis, we created the mutated cDNA that was transfected, along with KCNJ3 cDNA, in mammalian cells. We also localized CYP11B2 in the excised adrenal gland with immunohistochemistry and immunofluorescence using an antibody specific to human CYP11B2. Whole-cell patch clamp recordings, CYP11B2 mRNA, aldosterone measurement, and molecular modeling were performed to characterize the novel KCNJ5-insT149 mutation. RESULTS: Compared with wild-type and mock-transfected adrenocortical cells, HAC15 cells expressing the mutant KCNJ5 showed increased CYP11B2 expression and aldosterone secretion. Mammalian cells expressing the mutated KCNJ5-insT149 channel exhibited a strong Na(+) inward current and, in parallel, a substantial rise in intracellular Ca(2+), caused by activation of voltage-gated Ca(2+) channels and reduced Ca(2+) elimination by Na(+)/Ca(2+) exchangers, as well as an increased production of aldosterone. CONCLUSIONS: This novel mutation shows pathological Na(+) permeability, membrane depolarization, raised cytosolic Ca(2+), and increased aldosterone synthesis. Hence, a novel KCNJ5 channelopathy located after the pore ?-helix preceding the selectivity filter causes constitutive secretion of aldosterone with ensuing resistant hypertension in a patient with a small APA. Twit Text FOAVip A novel KCNJ5-insT149 somatic mutation close to, but outside, the selectivity filter causes resistant hypertension by loss of selectivity for potassium ????J Clin Endocrinol Metab http://www.kidney.de/pget.php?&tw=1&pmid=25057880 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=25057880 #FOAvip English Wikipedia <ref>{{Cite pmid|25057880 }}</ref> A novel KCNJ5-insT149 somatic mutation close to, but outside, the selectivity filter causes resistant hypertension by loss of selectivity for potassium #MMPMID25057880 Kuppusamy M ; Caroccia B ; Stindl J ; Bandulik S ; Lenzini L ; Gioco F ; Fishman V ; Zanotti G ; Gomez-Sanchez C ; Bader M ; Warth R ; Rossi GP J Clin Endocrinol Metab 2014[Sep]; 99 (9 ): E1765-73 PMID25057880 show ga CONTEXT: Understanding the function of the KCNJ5 potassium channel through characterization of naturally occurring novel mutations is key for dissecting the mechanism(s) of autonomous aldosterone secretion in primary aldosteronism. OBJECTIVE: We sought for such novel KCNJ5 channel mutations in a large database of patients with aldosterone-producing adenomas (APAs). METHODS: We discovered a novel somatic c.446insAAC insertion, resulting in the mutant protein KCNJ5-insT149, in a patient with severe drug-resistant hypertension among 195 consecutive patients with a conclusive diagnosis of APA, 24.6% of whom showed somatic KCNJ5 mutations. By site-directed mutagenesis, we created the mutated cDNA that was transfected, along with KCNJ3 cDNA, in mammalian cells. We also localized CYP11B2 in the excised adrenal gland with immunohistochemistry and immunofluorescence using an antibody specific to human CYP11B2. Whole-cell patch clamp recordings, CYP11B2 mRNA, aldosterone measurement, and molecular modeling were performed to characterize the novel KCNJ5-insT149 mutation. RESULTS: Compared with wild-type and mock-transfected adrenocortical cells, HAC15 cells expressing the mutant KCNJ5 showed increased CYP11B2 expression and aldosterone secretion. Mammalian cells expressing the mutated KCNJ5-insT149 channel exhibited a strong Na(+) inward current and, in parallel, a substantial rise in intracellular Ca(2+), caused by activation of voltage-gated Ca(2+) channels and reduced Ca(2+) elimination by Na(+)/Ca(2+) exchangers, as well as an increased production of aldosterone. CONCLUSIONS: This novel mutation shows pathological Na(+) permeability, membrane depolarization, raised cytosolic Ca(2+), and increased aldosterone synthesis. Hence, a novel KCNJ5 channelopathy located after the pore ?-helix preceding the selectivity filter causes constitutive secretion of aldosterone with ensuing resistant hypertension in a patient with a small APA. |Adenoma/*genetics/metabolism [MESH] |Adrenal Cortex/cytology/metabolism [MESH] |Adrenocortical Adenoma/*genetics/metabolism [MESH] |Aged [MESH] |Aldosterone/metabolism [MESH] |Antihypertensive Agents/therapeutic use [MESH] |Cell Line [MESH] |Drug Resistance [MESH] |G Protein-Coupled Inwardly-Rectifying Potassium Channels/*genetics/metabolism [MESH] |Humans [MESH] |Hyperaldosteronism/*genetics/metabolism [MESH] |Hypertension/drug therapy/*genetics/metabolism [MESH] |Male [MESH] |Point Mutation [MESH]A novel KCNJ5-insT149 somatic mutation close to, but outside, the sele(epmc).pdf DeepDyve Pubget Overpricing