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: 33.61). 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 (Ca2+) 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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Available from: Elias Lolis, Sep 26, 2015
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    • "We will focus this review on the mechanism and structural details of polyamine block of the Kir2 subfamily channels (which are particularly sensitive to polyamines), as well as some of the details of their physiological roles and disruption in genetic channelopathies. It is noteworthy that “weak” inward rectifiers (with shallow voltage dependence, and weak polyamine sensitivity) play many important physiological roles, impacting diverse processes such as hormone secretion (Koster et al., 2000; Choi et al., 2011), ion transport in the nephron (Simon et al., 1996), and control of ionic gradients in the inner ear (Scholl et al., 2009). Thus, we also refer readers to a recent broad review that provides an overview of the structure, function, and physiology of the entire Kir channel family as an excellent starting point for further discussion of other Kir channel types (Hibino et al., 2010). "
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    ABSTRACT: Inwardly-rectifying potassium (Kir) channels contribute to maintenance of the resting membrane potential and regulation of electrical excitation in many cell types. Strongly rectifying Kir channels exhibit a very steep voltage dependence resulting in silencing of their activity at depolarized membrane voltages. The mechanism underlying this steep voltage dependence is blockade by endogenous polyamines. These small multifunctional, polyvalent metabolites enter the long Kir channel pore from the intracellular side, displacing multiple occupant ions as they migrate to a stable binding site in the transmembrane region of the channel. Numerous structure-function studies have revealed structural elements of Kir channels that determine their susceptibility to polyamine block, and enable the steep voltage dependence of this process. In addition, various channelopathies have been described that result from alteration of the polyamine sensitivity or activity of strongly rectifying channels. The primary focus of this article is to summarize current knowledge of the molecular mechanisms of polyamine block, and provide some perspective on lingering uncertainties related to this physiologically important mechanism of ion channel blockade. We also briefly review some of the important and well understood physiological roles of polyamine sensitive, strongly rectifying Kir channels, primarily of the Kir2 family.
    Frontiers in Physiology 08/2014; 5:325. DOI:10.3389/fphys.2014.00325 · 3.53 Impact Factor
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    • "DNA sequencing and mutations in KCNJ5 APA cases (n = 74) were submitted to PCR using a KCNJ5 primer (forward 5 0 -CGA CCA AGA GTG GAT TCC TT- 0 3, reverse 5 0 -AGG GTC TCC GCT CTC TTC TT- 0 3) as described by our group [11]. Analysis of the purified DNA was carried out with a Abi Prism 310 genetic analyser (Applied Biosystems, Foster City, CA, USA), and mutations at the G151R and L168R regions of the KCNJ5 gene were analyzed as described [4] "
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    ABSTRACT: Calcium channel blockers can efficiently be used in the treatment of primary aldosteronism (PA) related hypertension, but details on the localization of calcium channels (CCs) in the human adrenal and its disorders, including PA, have remained unclear. Therefore, in this study we analyzed the known α subunits of L-, N-, and T-type CCs in 74 adrenocortical aldosterone-producing adenomas (APA) and 16 cortisol-producing adenomas (CPA) using quantitative RT-PCR (qPCR). We also examined the status of L-(CaV1.2, CaV1.3), N-(CaV2.2) and T-(CaV3.2) CC subunits in five non-pathological adrenals (NA), five idiopathic hyperaldosteronism (IHA) cases, and 50 APA using immunohistochemistry. After qPCR evaluation, only CaV1.2, CaV1.3, CaV2.2, and CaV3.2 mRNA levels could be detected in APA and CPA. Among those, only CaV3.2 mRNA levels were significantly correlated with plasma aldosterone levels (P=0.0031), CYP11B2 expression levels (P<0.0001) and the presence of KCNJ5 mutations (P=0.0019) in APA. The immunolocalization of CCs in NA and IHA was detected in the zona glomerulosa (ZG), with a predominance of CaV3.2 in APA. These findings suggest that different types of CC can be involved in calcium-related aldosterone biosynthesis.
    The Journal of Steroid Biochemistry and Molecular Biology 08/2014; pii: S0960-0760(14):00191-5. DOI:10.1016/j.jsbmb.2014.08.012 · 3.63 Impact Factor
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    • "William F Young called this rediscovery of PA’s prevalence and morbidity as the “renaissance of a syndrome.”14 However, the pathophysiology of PA remained unclear until Choi et al made an important breakthrough by reporting the presence of mutations in the gene encoding the inwardly rectifying potassium channel Kir3.4 (KCNJ5) in patients with aldosterone-producing adenoma.15 In the last two years, the use of whole genome sequencing has led to a revolution in PA diagnosis and research. "
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    ABSTRACT: Primary aldosteronism is the most common cause of secondary hypertension. The syndrome accounts for 10% of all cases of hypertension and is primarily caused by bilateral adrenal hyperplasia or aldosterone-producing adenoma. Over the last few years, the use of exome sequencing has significantly improved our understanding of this syndrome. Somatic mutations in the KCNJ5, ATP1A1, ATP2B3 or CACNA1D genes are present in more than half of all cases of aldosterone-producing adenoma (~40%, ~6%, ~1% and ~8%, respectively). Germline gain-of-function mutations in KCNJ5 are now known to cause familial hyperaldosteronism type III, and an additional form of genetic hyperaldosteronism has been reported in patients with germline mutations in CACNA1D. These genes code for channels that control ion homeostasis across the plasma membrane of zona glomerulosa cells. Moreover, all these mutations modulate the same pathway, in which elevated intracellular calcium levels lead to aldosterone hyperproduction and (in some cases) adrenal cell proliferation. From a clinical standpoint, the discovery of these mutations has potential implications for patient management. The mutated channels could be targeted by drugs, in order to control hormonal and overgrowth-related manifestations. Furthermore, some of these mutations are associated with high cell turnover and may be amenable to diagnosis via the sequencing of cell-free (circulating) DNA. However, genotype-phenotype correlations in patients harboring these mutations have yet to be characterized. Despite this recent progress, much remains to be done to elucidate the yet unknown mechanisms underlying sporadic bilateral adrenal hyperplasia.
    The Application of Clinical Genetics 04/2014; 7:67-79. DOI:10.2147/TACG.S45620
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