Genetic aspects of primary hyperaldosteronism

Korzynska, Weronika; Jodkowska, Anna; Gosławska, Katarzyna; Bogunia‐Kubik, Katarzyna; Mazur, Grzegorz

doi:10.17219/acem/69390

Cited by 8 publications

(7 citation statements)

References 44 publications

(92 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In physiological conditions, aldosterone secretion is regulated by the interplay between angiotensin II and plasma K + concentration, [K + ] (10). Angiotensin activates angiotensin II type 1 receptor, leading to depolarization of aldosterone-secreting cells through inhibition of K + channels and Na + /K + pump (11,12). Consequently, L-and T-type voltage-gated Ca 2+ channels (VGCC) open, Ca 2+ enters the cell and activates aldosterone secretion.…”

Section: Introductionmentioning

confidence: 99%

“…PA accounts for 90% of secondary hypertension cases, approximately 10% of hypertensive patients worldwide (14). The main causes of PA are somatic and germline mutations in KCNJ5, CACNA1D, CACNA1H, ATP1A1, ATP2B3, CTNNB1, ARMC5 genes (12). Sporadic and familial mutations in KCNJ5 account for up to 70% of PA cases, often accompanied by adrenal adenoma (14,15).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A revised mechanism of action of hyperaldosteronism-linked mutations in cytosolic domains of GIRK4 (KCNJ5)

Shalomov

Handklo-Jamal

Reddy

et al. 2019

Preprint

View full text Add to dashboard Cite

ClassificationBiological Sciences: Physiology. AbstractG-protein gated, inwardly rectifying potassium channels (GIRK) mediate inhibitory transmission in brain, heart, and adrenal cortex. GIRK4 (KCNJ5) subunits are abundant in the heart and adrenal cortex. Multiple mutations of KCNJ5 cause primary aldosteronism (PA). According to a leading concept, mutations in the pore region of GIRK4 cause loss of K + selectivity; the ensuing Na + influx depolarizes zona glomerulosa cells and activates voltage gated Ca 2+ channels, inducing hypersecretion of aldosterone. The concept of selectivity loss has been extended to mutations in cytosolic domains of GIRK4 channels, remote from the pore region. We expressed GIRK4R52H, GIRK4E246K, and GIRK4G247R mutants in Xenopus oocytes and human adrenocortical carcinoma cell line (HAC15). Whole-cell currents of heterotetrameric GIRK1/4R52H and GIRK1/4E246K (but not GIRK1/4G247R) channels were greatly reduced compared to GIRK1/4WT. Nevertheless, all heterotetrameric mutants retained full K + selectivity and inward rectification. When expressed as homotetramers, only GIRK4WT, but none of the mutants, produced wholecell currents. Confocal imaging, single channel and Förster Resonance Energy Transfer (FRET) analyses showed: 1) reduction of membrane abundance of all mutated channels, especially as homotetramers, 2) impaired interaction with Gβγ subunits, and 3) reduced open probability of GIRK1/4R52H. VU0529331, a GIRK4 opener, activated homotetrameric GIRK4G247R channels, but not GIRK4R52H and GIRK4E246K. Our results suggest impaired gating (GIRK4R52H) and expression in plasma membrane (all mutants). We suggest that, contrary to the previously proposed mechanism, R52H and E246K mutants are loss-offunction rather than gain-of-function/selectivity-loss mutants. Hence, GIRK4 openers may be a potential course of treatment for patients with cytosolic N-and C-terminal mutations. Significance StatementMutations in KCNJ5 gene, which encodes for the GIRK4 subunit of G-protein inwardly rectifying K+ channels, are the main cause of primary aldosteronism, a major contributor to secondary hypertension. We report that three mutations in the cytosolic domain of GIRK4 cause loss-of-function, contrary to the prevailing concept that these mutations cause loss of selectivity and subsequent depolarization, i.e. essentially gainof-function. Our findings correct the existing misconception regarding the biophysical mechanism that impairs the channel function, and may provide indications for future personalized treatment of the disease.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A revised mechanism of action of hyperaldosteronism-linked mutations in cytosolic domains of GIRK4 (KCNJ5)

Shalomov

Handklo-Jamal

Reddy

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…In about 50% of patients with aldosterone-producing APA, somatic mutations of the KCNJ5 gene have been demonstrated, as a result of which K + channels are less selective, allowing inflow of Na + ions and then Ca 2+ ions into the cells of the adrenal glomerular layer, which increases the synthesis of aldosterone [ 46 ]. Moreover, a recent meta-analysis including 13 studies for a total of 1636 patients presented the overall prevalence of KCNJ5 mutations as 43%, with higher prevalence in East Asian populations compared to Western populations [ 47 ].…”

Section: Genetic Basis Of Pamentioning

confidence: 99%

“…The ATP1A1 gene is located on chromosome 1p21 and encodes ATPase Na + /K + transporting subunit alpha 1. Na + /K + -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na + and K + across the plasma membrane [ 46 ]. These gradients are essential for osmoregulation, for Na-coupled transport of a variety of organic and inorganic molecules, and for the electrical excitability of nerve and muscle.…”

Section: Genetic Basis Of Pamentioning

confidence: 99%

Progress on Genetic Basis of Primary Aldosteronism

et al. 2021

View full text Add to dashboard Cite

Primary aldosteronism (PA) is a heterogeneous group of disorders caused by the autonomous overproduction of aldosterone with simultaneous suppression of plasma renin activity (PRA). It is considered to be the most common endocrine cause of secondary arterial hypertension (HT) and is associated with a high rate of cardiovascular complications. PA is most often caused by a bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA); rarer causes of PA include genetic disorders of steroidogenesis (familial hyperaldosteronism (FA) type I, II, III and IV), aldosterone-producing adrenocortical carcinoma, and ectopic aldosterone-producing tumors. Over the last few years, significant progress has been made towards understanding the genetic basis of PA, classifying it as a channelopathy. Recently, a growing body of clinical evidence suggests that mutations in ion channels appear to be the major cause of aldosterone-producing adenomas, and several mutations within the ion channel encoding genes have been identified. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D) have been identified in nearly 60% of the sporadic APAs, while germline mutations in KCNJ5 and CACNA1H have been reported in different subtypes of familial hyperaldosteronism. These new insights into the molecular mechanisms underlying PA may be associated with potential implications for diagnosis and therapy.

show abstract

“…For the last several years, the introduction of new-generation sequencing has improved the understanding of the molecular and genetic basis of sporadic primary aldosteronism (19,20). The questions are at least two.…”

Section: Bilateral Primary Aldosteronism Still Idiopathic or Not?mentioning

confidence: 99%

Primary aldosteronism – the expanding spectrum of unsolved practical issues

Łebek-Szatańska

Papierska²

2020

View full text Add to dashboard Cite

Primary aldosteronism is the most frequent cause of hormonal hypertension. Recent findings support the concept of continuous spectrum of autonomous aldosterone secretion with mild or subclinical forms being even more common than was suspected. Assumptions emerge that a considerable number of low-renin hypertensives might actually have aldosterone overproduction. However, the awareness of the disease and its consequences is still unsatisfactory. Nowadays experts are still trying to manage some unanswered questions and on-going debate on who should be screened for primary aldosteronism and how to do so.

show abstract

Genetic aspects of primary hyperaldosteronism

Cited by 8 publications

References 44 publications

A revised mechanism of action of hyperaldosteronism-linked mutations in cytosolic domains of GIRK4 (KCNJ5)

A revised mechanism of action of hyperaldosteronism-linked mutations in cytosolic domains of GIRK4 (KCNJ5)

Progress on Genetic Basis of Primary Aldosteronism

Primary aldosteronism – the expanding spectrum of unsolved practical issues

Contact Info

Product

Resources

About