Several Types of Somatic Mutations Induce Autonomous Production of Aldosterone in Primary Aldosteronism
Journal Title: Journal of Endocrinology and Diabetes - Year 2015, Vol 2, Issue 1
Abstract
It is well known that primary aldosteronism (PA) is the most common form of secondary hypertension, and also that aldosterone-producing adenoma (APA) and bilateral hyperaldosteronism (idiopathic hyperaldosteronism: IHA) are the most common forms of PA. Now, genetic analysis for solving pathogenesis of PA is progressing. Somatic gene mutations of the selectivity filter of the potassium K(+) channel KCNJ5 were recently detected in APA in patients with sporadic PA [1]. These mutations were reported to produce increased sodium (Na+) conductance and cell depolarization resulting in autonomous aldosterone production in the APA [1]. It was already reported that somatic G151R or L168R mutations were found in 40% of APA associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia [2]. Moreover, it had recently been reported that the TASK-2 channel lower expression represents universal characteristics of APA, associated with a higher expression of hsa-miR-23 and hsa-miR-34. The blunted TASK-2 activity induced an increase in the production of aldosterone in vitro and the expression of steroidogenic acute regulatory protein and CYP11B2.Thus, the lower expression of TASK-2 channel in APA cells can explain autonomous production of aldosterone in PA [3]. Gomez-Sanchez [4] had recently summarized that somatic mutations of the selectivity filter of the Kir3.4 channel in APA results in loss of selectivity for K(+) and entry of sodium, resulting in membrane depolarization, calcium mobilization, increased CYP11B2 expression, and hyperaldosteronism. Thus, he emphasized that APA is caused by channelopathies inducing an increase in aldosterone synthesis [4]. Germ cell mutations of KCNJ5 cause familial hyperaldosteronism type 3, which is associated with adrenal zona glomerulosa hyperplasia, rather than adenoma [5,6]. Less commonly, somatic mutations of the sodium-potassium ATPase, calcium ATPase, or the calcium channel (calcium channel voltage-dependent L type alpha 1D) have been found in some APAs. It was also reported that somatic mutations in ATP1A1, ATP2B3, and KCNJ5 were present in 6.3%, 0.9%, and 39.3% of APAs, respectively, and included 2 novel mutations (Na (+)/K (+)-ATPase p.Gly99Arg and GIRK4 p.Trp126Arg) [7]. CYP11B2 gene expression was higher in APAs harboring ATP1A1 and ATP2B3 mutations compared with those without these or KCNJ5 mutations
Authors and Affiliations
Tetsuo Nishikawa, Takumi Kitamoto, Yoko Matsuzawa, Jun Saito, Masao Omura
Keywords
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- EP ID EP333124
- DOI 10.15226/2374-6890/2/1/00110
- Views 111
- Downloads 0
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