GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism

Monticone, Silvia; Buffolo, Fabrizio; Tetti, Martina; Veglio, Franco; Pasini, Barbara; Mulatero, Paolo

doi:10.1530/eje-17-0946

Cited by 46 publications

(22 citation statements)

References 66 publications

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“…Systematic review of the reported cases revealed that hypertension is present in 92.4% of the patients, hypokalemia (defined as serum K + <3.5 mmol/L) in 71.8% and hypoaldosteronemia (defined as serum aldosterone <5 ng/dL) in 58.2% of the cases. As reported for other forms of monogenic hypertension [ 89 , 90 ], this variability is not only observed between kindreds carrying different mutations, but also between affected members of the same family ( Table 1 ). It is likely that both environmental and genetic factors, including Na + intake and polymorphisms in genes involved in Na + handling could influence the phenotypic manifestation of the disease [ 63 ].…”

Section: Liddle Syndromesupporting

confidence: 69%

Liddle Syndrome: Review of the Literature and Description of a New Case

Tetti

Monticone

Burrello

et al. 2018

IJMS

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Liddle syndrome is an inherited form of low-renin hypertension, transmitted with an autosomal dominant pattern. The molecular basis of Liddle syndrome resides in germline mutations of the SCNN1A, SCNN1B and SCNN1G genes, encoding the α, β, and γ-subunits of the epithelial Na+ channel (ENaC), respectively. To date, 31 different causative mutations have been reported in 72 families from four continents. The majority of the substitutions cause an increased expression of the channel at the distal nephron apical membrane, with subsequent enhanced renal sodium reabsorption. The most common clinical presentation of the disease is early onset hypertension, hypokalemia, metabolic alkalosis, suppressed plasma renin activity and low plasma aldosterone. Consequently, treatment of Liddle syndrome is based on the administration of ENaC blockers, amiloride and triamterene. Herein, we discuss the genetic basis, clinical presentation, diagnosis and treatment of Liddle syndrome. Finally, we report a new case in an Italian family, caused by a SCNN1B p.Pro618Leu substitution.

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Section: Liddle Syndromesupporting

confidence: 69%

Liddle Syndrome: Review of the Literature and Description of a New Case

Tetti

Monticone

Burrello

et al. 2018

IJMS

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“…The mechanisms leading to BHA remain poorly understood with the exception of the rare familial forms where germline mutations in CACNA1D, CACNA1H, KCNJ5 and CLCN2 have each been shown to cause bilateral adrenal aldosterone production [72][73][74]. The underlying causes of sporadic (non-familial) forms of CT-negative BHA often termed IHA still remain to be clarified.…”

Section: Apcc In Preclinical and Overt Primary Aldosteronismmentioning

confidence: 99%

The Potential Role of Aldosterone-Producing Cell Clusters in Adrenal Disease

Lim

Rainey

2020

Horm Metab Res

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Primary aldosteronism (PA) is the most common cause of secondary hypertension. The hallmark of PA is adrenal production of aldosterone under suppressed renin conditions. PA subtypes include adrenal unilateral and bilateral hyperaldosteronism. Considerable progress has been made in defining the role for somatic gene mutations in aldosterone-producing adenomas (APA) as the primary cause of unilateral PA. This includes the use of next-generation sequencing (NGS) to define recurrent somatic mutations in APA that disrupt calcium signaling, increase aldosterone synthase (CYP11B2) expression, and aldosterone production. The use of CYP11B2 immunohistochemistry on adrenal glands from normal subjects, patients with unilateral and bilateral PA has allowed the identification of CYP11B2-positive cell foci, termed aldosterone-producing cell clusters (APCC). APCC lie beneath the adrenal capsule and like APA, many APCC harbor somatic gene mutations known to increase aldosterone production. These findings suggest that APCC may play a role in pathologic progression of PA. Herein, we provide an update on recent research directed at characterizing APCC and also discuss the unanswered questions related to the role of APCC in PA.

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“…However, despite this selection pressure not all predicted high confidence CACNA1D APA and APCC mutations may strongly contribute to disease risk because other, yet unknown mechanisms could be responsible. Notably, a substantial fraction of excessive aldosterone production in APAs is due to mechanisms not explained by somatic variants in known genes [24]. This emphasizes the need for further functional characterization of CACNA1D APA mutations to verify their causative roles.…”

Section: Introductionmentioning

confidence: 99%

Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels

et al. 2018

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Recently, we and others identified somatic and germline de novo gain-of-function mutations in CACNA1D, the gene encoding the α1-subunit of voltage-gated Cav1.3 Ca2+-channels. While somatic mutations identified in aldosterone producing adenomas (APAs) underlie treatment-resistant hypertension, germline CACNA1D mutations are associated with a neurodevelopmental disorder characterized by a wide symptomatic spectrum, including autism spectrum disorder. The number of newly identified CACNA1D missense mutations is constantly growing, but their pathogenic potential is difficult to predict in silico, making functional studies indispensable to assess their contribution to disease risk.Here we report the functional characterization of previously identified CACNA1D APA mutations F747L and M1354I using whole-cell patch-clamp electrophysiology upon recombinant expression in tsA-201 cells. We also investigated if alternative splicing of Cav1.3 affects the aberrant gating of the previously characterized APA mutation R990H and two mutations associated with autism spectrum disorder (A479G and G407R). Splice-variant dependent gating changes are of particular interest for germline mutations, since the relative expression of Cav1.3 splice variants differs across different tissues and within brain regions and might therefore result in tissue-specific phenotypes. Our data revealed a complex gain-of-function phenotype for APA mutation F747L confirming its pathogenic role. Furthermore, we found splice-variant dependent gating changes in R990H, A749G and G407R. M1354I did not change channel function of Cav1.3 splice variants and should therefore be considered a rare non-pathogenic variant until further proof for its pathogenicity is obtained. Our new findings together with previously published data allow classification of pathogenic CACNA1D mutations into four categories based on prototypical functional changes.

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GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism

Cited by 46 publications

References 66 publications

Liddle Syndrome: Review of the Literature and Description of a New Case

Liddle Syndrome: Review of the Literature and Description of a New Case

The Potential Role of Aldosterone-Producing Cell Clusters in Adrenal Disease

Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels

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GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism

Cited by 46 publications

References 66 publications

Liddle Syndrome: Review of the Literature and Description of a New Case

Liddle Syndrome: Review of the Literature and Description of a New Case

The Potential Role of Aldosterone-Producing Cell Clusters in Adrenal Disease

Gating defects of disease-causing de novo mutations in Cav1.3 Ca2+ channels

Contact Info

Product

Resources

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Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels