Familial hyperaldosteronism type III

Monticone, Silvia; Tetti, Martina; Burrello, Jacopo; Buffolo, Fabrizio; Giovanni, R. De; Veglio, Franco; Williams, Tracy Ann; Mulatero, Paolo

doi:10.1038/jhh.2017.34

Cited by 40 publications

(33 citation statements)

References 35 publications

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“…It is widely accepted that this results in depolarization caused by the influx of Na + and a consequent influx of Ca 2+ through L-and T-type VGCCs followed by constitutive aldosterone secretion and hypertension (17,18). Since 2011, additional PA-linked mutations were discovered in KCNJ5 gene, in the pore region or in the cytosolic N-and C-terminal domains of GIRK4 (16,19,20).…”

Section: Introductionmentioning

confidence: 99%

“…Sporadic and familial mutations in KCNJ5 account for up to 70% of PA cases, often accompanied by adrenal adenoma (14,15). KCNJ5 germline mutations cause familial hyperaldosteronism type III, out of four types (16). In 2011, Choi et al (6) showed that PA-causing mutations in the GYG motif of the selectivity filter (G151R) or in close proximity to it (T158A and L168R) in GIRK4 cause a loss of selectivity for K + , yielding K + /Na + non-selective GIRK4 and GIRK1/4 channels (6).…”

Section: Introductionmentioning

confidence: 99%

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

Shalomov

Handklo-Jamal

Reddy

et al. 2019

Preprint

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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.

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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

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“…KCNJ5 germline mutations associated with FH-III have been reported (Figure 2), for a total of 12 families and 22 affected family members (29). Notably, none of the further reported cases displayed the peculiar hormonal phenotype described by Geller et al (24).…”

mentioning

confidence: 99%

GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism

Monticone

Buffolo

Tetti

et al. 2018

European Journal of Endocrinology

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2 AbstractAldosterone is the main mineralocorticoid hormone in humans and plays a key role in maintaining water and electrolyte homeostasis. Primary aldosteronism (PA), characterized by autonomous aldosterone overproduction by the adrenal glands, affects 6% of the general hypertensive population and can be either sporadic or familial. Aldosterone producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) are the two most frequent subtypes of sporadic PA, and 4 forms of familial hyperaldosteronism (FH-I to FH-IV) have been identified. Over the last six years the introduction of next-generation sequencing has significantly improved our understanding of the molecular mechanisms responsible for autonomous aldosterone overproduction in both sporadic and familial PA. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D), differently implicated in intracellular ion homeostasis, have been identified in nearly 60% of the sporadic APAs. Germline mutations in KCNJ5 and CACNA1H cause FH-III and FH-IV, respectively, while germline mutations in CACNA1D cause the rare PASNA syndrome, featuring primary aldosteronism seizures and neurological abnormalities. Further studies are warranted to identify the molecular mechanisms underlying BAH and FH-II, the most common forms of sporadic and familial PA whose molecular basis has yet to be uncovered.

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“…FH‐III was reported as a novel form of PA in 2008 and its molecular basis was uncovered in 2011, as a germline mutation of the KCNJ5 gene, encoding for the inward rectifying K + channel GIRK4. Twelve families and six germline mutations have been reported so far: most often affected patients display an extremely severe form of PA that requires bilateral adrenalectomy to control blood pressure . The Endocrine Society guideline recommends the genetic testing for FH‐III ( KCNJ5 target gene sequencing) in all patients with onset of PA at a very young age …”

Section: Primary Aldosteronismmentioning

confidence: 99%

“…Twelve families and six germline mutations have been reported so far: most often affected patients display an extremely severe form of PA that requires bilateral adrenalectomy to control blood pressure. 56 The Endocrine Society guideline recommends the genetic testing for…”

Section: Familial Primary Aldosteronismmentioning

confidence: 99%

Diagnostic approach to low‐renin hypertension

Monticone

Losano

Tetti

et al. 2018

Clinical Endocrinology

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Renin-angiotensin-aldosterone system (RAAS) plays a crucial role in maintaining water and electrolytes homoeostasis, and its deregulation contributes to the development of arterial hypertension. Since the historical description of the "classical" RAAS, a dramatic increase in our understanding of the molecular mechanisms underlying the development of both essential and secondary hypertension has occurred. Approximatively 25% of the patients affected by arterial hypertension display low-renin levels, a definition that is largely arbitrary and depends on the investigated population and the specific characteristics of the assay. Most often, low-renin levels are expression of a physiological response to sodium-volume overload, but also a significant number of secondary hereditary or acquired conditions falls within this category. In a context of suppressed renin status, the concomitant examination of plasma aldosterone levels (which can be inappropriately elevated, within the normal range or suppressed) and plasma potassium are essential to formulate a differential diagnosis. To distinguish between the different forms of low-renin hypertension is of fundamental importance to address the patient to the proper clinical management, as each subtype requires a specific and targeted therapy. The present review will discuss the differential diagnosis of the most common medical conditions manifesting with a clinical phenotype of low-renin hypertension, enlightening the novelties in genetics of the familial forms.

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Familial hyperaldosteronism type III

Cited by 40 publications

References 35 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)

GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism

Diagnostic approach to low‐renin hypertension

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