A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism

Fernandes-Rosa, Fábio Luiz; Daniil, Georgios; Orozco, Ian J.; Göppner, Corinna; Zein, Rami El; Jain, Vandana; Boulkroun, Sheerazed; Jeunemaı̂tre, Xavier; Amar, Laurence; Lefebvre, Henri; Schwarzmayr, Thomas; Strom, Tim M.; Jentsch, Thomas J.; Zennaro, Maria‐Christina

doi:10.1038/s41588-018-0053-8

Cited by 180 publications

(184 citation statements)

References 42 publications

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“…Loss-of-function mutations in CLCN2 are associated with leukoencephalo pathy 123 , and, controversially, with epilepsy 124, 125 ; therefore, it is plausible that activation of CLCN2 might serve to enhance cognitive function. By contrast, gain of function mutations 126 are associated with primary aldosteronism and subsequent hypertension, without cognitive impairment. The only drug with such a function identified by CMAP search was lubiprostone 127 , which is utilized for constipation and has unknown activity in the CNS.…”

Section: Discussionmentioning

confidence: 94%

Identifying Nootropic Drug Targets via Large-Scale Cognitive GWAS and Transcriptomics

Lam

Chen

Xia

et al. 2020

Preprint

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BackgroundCognitive traits demonstrate significant genetic correlations with many psychiatric disorders and other health-related traits. Many neuropsychiatric and neurodegenerative disorders are marked by cognitive deficits. Therefore, genome-wide association studies (GWAS) of general cognitive ability might suggest potential targets for nootropic drug repurposing. Our previous effort to identify “druggable genes” (i.e., GWAS-identified genes that produce proteins targeted by known small molecules) was modestly powered due to the small cognitive GWAS sample available at the time. Since then, two large cognitive GWAS meta-analyses have reported 148 and 205 genome-wide significant loci, respectively. Additionally, large-scale gene expression databases, derived from post-mortem human brain, have recently been made available for GWAS annotation. Here, we 1) reconcile results from these two cognitive GWAS meta-analyses to further enhance power for locus discovery; 2) employ several complementary transcriptomic methods to identify genes in these loci with variants that are credibly associated with cognition; and 3) further annotate the resulting genes to identify “druggable” targets.MethodsGWAS summary statistics were harmonized and jointly analysed using Multi-Trait Analysis of GWAS [MTAG], which is optimized for handling sample overlaps. Downstream gene identification was carried out using MAGMA, S-PrediXcan/S-TissueXcan Transcriptomic Wide Analysis, and eQTL mapping, as well as more recently developed methods that integrate GWAS and eQTL data via Summary-statistics Mendelian Randomization [SMR] and linkage methods [HEIDI], Available brain-specific eQTL databases included GTEXv7, BrainEAC, CommonMind, ROSMAP, and PsychENCODE. Intersecting credible genes were then annotated against multiple chemoinformatic databases [DGIdb, KI, and a published review on “druggability”].ResultsUsing our meta-analytic data set (N = 373,617) we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. 26 genes were associated with general cognitive ability via SMR, 16 genes via STissueXcan/S-PrediXcan, 47 genes via eQTL mapping, and 68 genes via MAGMA pathway analysis. The use of the HEIDI test permitted the exclusion of candidate genes that may have been artifactually associated to cognition due to linkage, rather than direct causal or indirect pleiotropic effects. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging on our various transcriptome and pathway analyses, as well as available chemoinformatic databases, we identified 16 putative genes that may suggest drug targets with nootropic properties.DiscussionResults converged on several categories of significant drug targets, including serotonergic and glutamatergic genes, voltage-gated ion channel genes, carbonic anhydrase genes, and phosphodiesterase genes. The current results represent the first efforts to apply a multi-method approach to integrate gene expression and SNP level data to identify credible actionable genes for general cognitive ability.

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Section: Discussionmentioning

confidence: 94%

Identifying Nootropic Drug Targets via Large-Scale Cognitive GWAS and Transcriptomics

Lam

Chen

Xia

et al. 2020

Preprint

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“…Criteria for the diagnosis of FH II are at least two first-degree members of the same family have confirmed PA and FH-I and familial hyperaldosteronism type-III (FH-III) have been excluded 76 . Six different mutations have been identified in CLCN2, encoding for a chloride channel, at conserved regions of the channel (p.M22K, p.G24D, p.Y26N, p.R172Q, p.delK362 and p.S865R) 77,78 . Mutation leads to open the channel and abolish the voltage dependency of the channel.…”

Section: Fh IImentioning

confidence: 99%

Genetic and molecular alterations in aldosterone producing adenomas

Dutta

2020

Linköping University Medical Dissertations

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Aldosterone producing tumors (APA, also known as Conn tumors) are adrenal tumors that overproduce aldosterone, a hormone that regulates the sodium levels in blood and contributes to blood pressure (BP) regulation. Excessive production of aldosterone causes hypertension and approximately 5-15% of hypertensive patients have hyperaldosteronism, known as primary aldosteronism (PA). Major causes of PA are bilateral adrenal hyperplasia (BAH) or aldosterone producing adenoma (APA) and about 30% of PA patients have APAs. In most cases, the disease is unilateral, in rare case bilateral. Patients with APA are often detected when they have elevated blood pressure (BP>160/100mmHg) or when BP cannot be controlled with drugs. Surgery dramatically normalizes or lowers BP in patients with APA.

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“…FH‐II is a not glucocorticoid remediable form of PA, traditionally considered as clinically and biochemically indistinguishable from a sporadic form . The genetic basis of some of the families affected by FH‐II has been very recently identified in germline mutations in the CLCN2 gene, encoding for the chloride channel ClC‐2, which is expressed in adrenal zona glomerulosa . The reported mutations facilitate the channel opening at the zona‐glomerulosa resting potential, resulting in cell membrane depolarization and up‐regulation of CYP11B2 expression .…”

Section: Primary Aldosteronismmentioning

confidence: 99%

“…53,54 The reported mutations facilitate the channel opening at the zona-glomerulosa resting potential, resulting in cell membrane depolarization and up-regulation of CYP11B2 expression. 53,54 The mode of transmission is autosomal dominant with incomplete penetrance. 54 Further studies are warranted to establish the impact (in term of prevalence) of CLCN2 mutations in FH.…”

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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A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism

Cited by 180 publications

References 42 publications

Identifying Nootropic Drug Targets via Large-Scale Cognitive GWAS and Transcriptomics

Identifying Nootropic Drug Targets via Large-Scale Cognitive GWAS and Transcriptomics

Genetic and molecular alterations in aldosterone producing adenomas

Diagnostic approach to low‐renin hypertension

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