Aldosterone-Producing Cell Clusters Frequently Harbor Somatic Mutations and Accumulate With Age in Normal Adrenals

Omata, Kei; Anand, Sharath Kumar; Hovelson, Daniel H.; Liu, Chia Jen; Yamazaki, Yuto; Nakamura, Yasuhiro; Ito, Sadayoshi; Satoh, Fumitoshi; Sasano, Hironobu; Rainey, William E.; Tomlins, Scott A.

doi:10.1210/js.2017-00134

Cited by 90 publications

(112 citation statements)

References 29 publications

(52 reference statements)

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“…Our findings with S652W (the loss-of-function mutation) emphasize that, in the case of CACNA1D, the amino acid position itself does not allow predictions about the disease risk of a variant, even if bioinformatics prediction tools provide high scores for protein damage. A high probability for pathogenicity can also be assumed if a variant identical to the germline mutation has also been found in at least two different individuals as a somatic mutation in an APA or an aldosterone-producing cellcluster [34,47,48]. Our report should raise awareness for the pathogenic potential of CACNA1D mutations, especially in patients without additional congenital endocrine symptoms as diagnostic features.…”

Section: Discussionmentioning

confidence: 76%

Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

et al. 2020

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Background: There is increasing evidence that de novo CACNA1D missense mutations inducing increased Cav1.3 Ltype Ca 2+-channel-function confer a high risk for neurodevelopmental disorders (autism spectrum disorder with and without neurological and endocrine symptoms). Electrophysiological studies demonstrating the presence or absence of typical gain-of-function gating changes could therefore serve as a tool to distinguish likely diseasecausing from non-pathogenic de novo CACNA1D variants in affected individuals. We tested this hypothesis for mutation S652L, which has previously been reported in twins with a severe neurodevelopmental disorder in the Deciphering Developmental Disorder Study, but has not been classified as a novel disease mutation. Methods: For functional characterization, wild-type and mutant Cav1.3 channel complexes were expressed in tsA-201 cells and tested for typical gain-of-function gating changes using the whole-cell patch-clamp technique. Results: Mutation S652L significantly shifted the voltage-dependence of activation and steady-state inactivation to more negative potentials (~13-17 mV) and increased window currents at subthreshold voltages. Moreover, it slowed tail currents and increased Ca 2+-levels during action potential-like stimulations, characteristic for gain-offunction changes. To provide evidence that only gain-of-function variants confer high disease risk, we also studied missense variant S652W reported in apparently healthy individuals. S652W shifted activation and inactivation to more positive voltages, compatible with a loss-of-function phenotype. Mutation S652L increased the sensitivity of Cav1.3 for inhibition by the dihydropyridine L-type Ca 2+-channel blocker isradipine by 3-4-fold. Conclusions and limitations Our data provide evidence that gain-of-function CACNA1D mutations, such as S652L, but not loss-of-function mutations, such as S652W, cause high risk for neurodevelopmental disorders including autism. This adds CACNA1D to the list of novel disease genes identified in the Deciphering Developmental Disorder Study. Although our study does not provide insight into the cellular mechanisms of pathological Cav1.3 signaling in neurons, we provide a unifying mechanism of gain-of-function CACNA1D mutations as a predictor for disease risk, which may allow the establishment of a more reliable diagnosis of affected individuals. Moreover, the increased sensitivity of S652L to isradipine encourages a therapeutic trial in the two affected individuals. This can address the important question to which extent symptoms are responsive to therapy with Ca 2+-channel blockers.

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Section: Discussionmentioning

confidence: 76%

Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

et al. 2020

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“…An alternative possibility is that this rare variant is not responsible for excess aldosterone production in APAs. This is supported by the fact that high-confidence somatic nonsynonymous CACNA1D variants that passed stringent in silico filtering have recently been described in APCCs [22] that are also unlikely to be pathogenic. This includes two premature stop codons.…”

Section: Discussionmentioning

confidence: 93%

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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“…Intriguingly, however, APCC were not found to have KCNJ5 mutations, the most common gene mutated in APA. Similarly, Omata et al demonstrated that APCC were common in Japanese non-hypertensive adrenals with 34 % harboring known aldosterone-driver somatic mutations with the most frequent mutations in CACNA1D but no KCNJ5 mutations were detected [51].…”

Section: Molecular Characterization Of Apccmentioning

confidence: 93%

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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Aldosterone-Producing Cell Clusters Frequently Harbor Somatic Mutations and Accumulate With Age in Normal Adrenals

Cited by 90 publications

References 29 publications

Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

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

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

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Aldosterone-Producing Cell Clusters Frequently Harbor Somatic Mutations and Accumulate With Age in Normal Adrenals

Cited by 90 publications

References 29 publications

Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

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

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

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