scholarly journals Adrenal Nodularity and Somatic Mutations in Primary Aldosteronism: One Node Is the Culprit?

2014 ◽  
Vol 99 (7) ◽  
pp. E1341-E1351 ◽  
Author(s):  
T. Dekkers ◽  
M. ter Meer ◽  
J. W. M. Lenders ◽  
A. R. M. Hermus ◽  
L. Schultze Kool ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Somatic Mutations

Abstract 277: Mutations in the KCNJ5 Gene Imply a Higher Lateralization Index at Adrenal Vein Sampling for Primary Aldosteronism

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Teresa M Seccia ◽  
Franco Mantero ◽  
Claudio Letizia ◽  
Maniselvan Kuppusamy ◽  
Marlena Barisa ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Somatic Mutations ◽  
Contralateral Side ◽  
Adrenal Vein ◽  
K Channel ◽  
Coding Region ◽  
Aldosterone Secretion ◽  
Adrenal Vein Sampling ◽  
Lateralization Index

Background. The mutations that affect the selectivity filter of the KCNJ5 K+ channel can play a role in triggering and/or maintaining aldosterone oversecretion in primary aldosteronism (PA). We therefore hypothesized that these somatic mutations can be associated with an increased aldosterone secretion from the APA, thus translating in raised plasma aldosterone concentrations (PAC) in the ipsilateral adrenal vein. Aim. To investigate if the lateralization index (LI) at adrenal vein sampling (AVS) is higher in the patients with an APA carrying the mutation (KCNJ5mut), as compared to those without the mutation (KCNJ5wt). Methods. Ninety-two consecutive PA patients who underwent AVS and received diagnosis of APA based on the four corners criteria were recruited. Unequivocal information on the presence or absence of the KCNJ5 mutations was available for each patient. The selectivity index (SI) was calculated as ratio between the right or left adrenal vein PCC (PCCside) and the infrarenal IVC PCC and a cutoff of 2.00 was used. The lateralization index (LI) was calculated in the bilaterally selective AVS as the ratio of PAC/PCC at the APA side to PAC/PCC at the contralateral side. We sequenced the KCNJ5 coding region spanning aminoacids 122 to 199, which include the selectivity filer. Results. The overall prevalence rate of KCNJ5 somatic mutations was 34%; G151R, L168R and T158A mutations were found in 19, 10 and 1 APA respectively. The G151E mutation was not found. The KCNJ5mut and KCNJ5wt groups were similar for gender, age, sK+ levels, while PAC and ARR were higher, and PRA lower (all p<0.05) in the KCNJ5 mut group. In the latter group the LI was higher than in the KCNJ5wt group (29.3± 6.7 vs 16.7±3.9, p< 0.02). This was due to a PAC/PCC ratio which was higher in the adrenal vein ipsilateral to the APA side and lower contralaterally in the KCNJ5mut group. Conclusions. These results provide direct in vivo evidence for a higher aldosterone secretion from APA carrying the KCNJ5 mutations, which translates into higher values of the LI, compared to the tumors without such mutations. Hence, the presence of these KCNJ5 mutations can affect the accuracy of the AVS-based diagnosis of the subtype of PA.

scholarly journals PRKACA Somatic Mutations Are Rare Findings in Aldosterone-Producing Adenomas

2016 ◽  
Vol 101 (8) ◽  
pp. 3010-3017 ◽  
Author(s):  
Yara Rhayem ◽  
Luis G. Perez-Rivas ◽  
Anna Dietz ◽  
Kerstin Bathon ◽  
Christian Gebhard ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Primary Aldosteronism ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Functional Characterization ◽  
Cushing's Syndrome ◽  
Antihypertensive Medications ◽  
Unilateral Adrenalectomy ◽  
Vitro Analysis

Context: Somatic mutations have been found causative for endocrine autonomy in aldosterone-producing adenomas (APAs). Whereas mutations of PRKACA (catalytic subunit of protein kinase A) have been identified in cortisol-producing adenomas, the presence of PRKACA variants in APAs is unknown, especially in those that display cosecretion of cortisol. Objective: The objective of the study was to investigate PRKACA somatic variants identified in APA cases. Design: Identification of PRKACA somatic variants in APAs by whole-exome sequencing followed by in vitro analysis of the enzymatic activity of PRKACA variants and functional characterization by double immunofluorescence of CYP11B2 and CYP11B1 expression in the corresponding tumor tissues. Setting and Patients: APA tissues were collected from 122 patients who underwent unilateral adrenalectomy for primary aldosteronism between 2005 and 2015 at a single institution. Results: PRKACA somatic mutations were identified in two APA cases (1.6%). One APA carried a newly identified p.His88Asp variant, whereas in a second case, a p.Leu206Arg mutation was found, previously described only in cortisol-producing adenomas with overt Cushing's syndrome. Functional analysis showed that the p.His88Asp variant was not associated with gain of function. Although CYP11B2 was strongly expressed in the p.His88Asp-mutated APA, the p.Leu206Arg carrying APA predominantly expressed CYP11B1. Accordingly, biochemical Cushing's syndrome was present only in the patient with the p.Leu206Arg mutation. After adrenalectomy, both patients improved with a reduced number of antihypertensive medications and normalized serum potassium levels. Conclusions: We describe for the first time PRKACA mutations as rare findings associated with unilateral primary aldosteronism. As cortisol cosecretion occurs in a subgroup of APAs, other molecular mechanisms are likely to exist.

scholarly journals Minireview: Potassium Channels and Aldosterone Dysregulation: Is Primary Aldosteronism a Potassium Channelopathy?

Endocrinology ◽  
2014 ◽  
Vol 155 (1) ◽  
pp. 47-55 ◽  
Author(s):  
Celso E. Gomez-Sanchez ◽  
Kenji Oki
Keyword(s):  
Potassium Channel ◽  
Calcium Channel ◽  
G Protein ◽  
Primary Aldosteronism ◽  
Somatic Mutations ◽  
Membrane Depolarization ◽  
Zona Glomerulosa ◽  
Aldosterone Secretion ◽  
K Channels ◽  
Inward Rectifying Potassium Channel

Primary aldosteronism is the most common form of secondary hypertension and has significant cardiovascular consequences. Aldosterone-producing adenomas (APAs) are responsible for half the cases of primary aldosteronism, and about half have mutations of the G protein-activated inward rectifying potassium channel Kir3.4. Under basal conditions, the adrenal zona glomerulosa cells are hyperpolarized with negative resting potentials determined by membrane permeability to K+ mediated through various K+ channels, including the leak K+ channels TASK-1, TASK-3, and Twik-Related Potassium Channel 1, and G protein inward rectifying potassium channel Kir3.4. Angiotensin II decreases the activity of the leak K+ channels and Kir3.4 channel and decreases the expression of the Kir3.4 channel, resulting in membrane depolarization, increased intracellular calcium, calcium-calmodulin pathway activation, and increased expression of cytochrome P450 aldosterone synthase (CYP11B2), the last enzyme for aldosterone production. Somatic mutations of the selectivity filter of the Kir3.4 channel in APA results in loss of selectivity for K+ and entry of sodium, resulting in membrane depolarization, calcium mobilization, increased CYP11B2 expression, and hyperaldosteronism. Germ cell mutations cause familial hyperaldosteronism type 3, which is associated with adrenal zona glomerulosa hyperplasia, rather than adenoma. Less commonly, somatic mutations of the sodium-potassium ATPase, calcium ATPase, or the calcium channel calcium channel voltage-dependent L type alpha 1D have been found in some APAs. The regulation of aldosterone secretion is exerted to a significant degree by activation of membrane K+ and calcium channels or pumps, so it is not surprising that the known causes of disorders of aldosterone secretion in APA have been channelopathies, which activate mechanisms that increase aldosterone synthesis.

scholarly journals Somatic Mutations in the KCNJ5 Gene Raise the Lateralization Index: Implications for the Diagnosis of Primary Aldosteronism by Adrenal Vein Sampling

2012 ◽  
Vol 97 (12) ◽  
pp. E2307-E2313 ◽  
Author(s):  
Teresa M. Seccia ◽  
Franco Mantero ◽  
Claudio Letizia ◽  
Maniselvan Kuppusamy ◽  
Brasilina Caroccia ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Somatic Mutations ◽  
Adrenal Vein ◽  
Adrenal Vein Sampling ◽  
Lateralization Index

scholarly journals Molecular mechanisms in primary aldosteronism

2019 ◽  
Vol 242 (3) ◽  
pp. R67-R79 ◽  
Author(s):  
Kelly De Sousa ◽  
Alaa B Abdellatif ◽  
Rami M El Zein ◽  
Maria-Christina Zennaro
Keyword(s):  
Arterial Hypertension ◽  
Adrenal Cortex ◽  
Primary Aldosteronism ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Type I ◽  
Adrenal Hyperplasia ◽  
New Genes ◽  
Aldosterone Production ◽  
Bilateral Adrenal Hyperplasia

Primary aldosteronism (PA) is the most common form and an under-diagnosed cause of secondary arterial hypertension, accounting for up to 10% of hypertensive cases and associated to increased cardiovascular risk. PA is caused by autonomous overproduction of aldosterone by the adrenal cortex. It is mainly caused by a unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. Excess aldosterone leads to arterial hypertension with suppressed renin, frequently associated to hypokalemia. Mutations in genes coding for ion channels and ATPases have been identified in APA, explaining the pathophysiology of increased aldosterone production. Different inherited genetic abnormalities led to the distinction of four forms of familial hyperaldosteronism (type I to IV) and other genetic defects very likely remain to be identified. Somatic mutations are identified in APA, but also in aldosterone-producing cell clusters (APCCs) in normal adrenals, in image-negative unilateral hyperplasia, in transitional lesions and in APCC from adrenals with bilateral adrenal hyperplasia (BAH). Whether these structures are precursors of APA or whether somatic mutations occur in a proliferative adrenal cortex, is still a matter of debate. This review will summarize our knowledge on the molecular mechanisms responsible for PA and the recent discovery of new genes related to early-onset and familial forms of the disease. We will also address new issues concerning genomic and proteomic changes in adrenals with APA and discuss adrenal pathophysiology in relation to aldosterone-producing structures in the adrenal cortex.

scholarly journals The results of immunohistochemical study of antibodies to CYP11B2 in primary hyperaldosteronism

2021 ◽  
Vol 18 (3) ◽  
pp. 245-253
Author(s):  
N. Yu. Romanova ◽  
L. S. Selivanova ◽  
N. M. Platonova ◽  
D. G. Beltsevich ◽  
E. A. Troshina
Keyword(s):  
Adrenal Cortex ◽  
Primary Aldosteronism ◽  
Somatic Mutations ◽  
Ct Scanning ◽  
Adrenal Tumors ◽  
Adrenocortical Adenoma ◽  
Loss Of Function ◽  
Functional Heterogeneity ◽  
Driver Genes ◽  
Tumor Area

Background: Aldosterone-producing adrenocortical adenoma (APA) is responsible for the majority of cases clinically diagnosed as primary aldosteronism. Aldosterone synthase (CYP11B2) is one of the enzymes that play essential roles in aldosterone synthesis and is involved in the pathogenesis of primary aldosteronism. Recent studies have demonstrated that various factors influence the expression and function of CYP11B2 in APA. In particular, somatic mutations, such as gain-of-function and loss-of-function mutations have been identified in several genes, each of which encodes a pivotal protein that affects the calcium signaling pathway, the expression of CYP11B2, and aldosterone production. On the other hand, CYP11B2 also catalyzes the conversion of cortisol to 18-hydroxycortisol and subsequently converts 18-hydroxycortisol to 18-oxocortisol. The article also discusses the clinical significance of 18-oxocortisol, an important biomarker for the diagnosis of primary aldosteronism. Somatic mutations in aldosterone-driver genes are strongly associated with CYP11B2 expression and have been only detected in the CYP11B2-positive tumor area, that indicating heterogeneous expression of CYP11B2 in tumor.Aim: to assess the functional heterogeneity of adrenal tumors in primary aldosteronismMaterials and methods: Retrospective evaluation adrenal tumors from patients with primary aldosteronism (n=20). According to CT unilateral macrohyperplasia was detected in 19 patients (95% of total), all of them were confirmed to have unilateral hyperproduction of aldosterone according to AVS. Selected tumors werestained with anty-CYP11B2 antibody. We evaluated the CYP11B2 expression in the adenoma and in the adjacent adrenal cortex.Results: Immunohistochemistry studies of the resected adrenals from 20 patients with PA operated due to unilateral production of aldosterone using CYP11B2 staining showed that 10 of those with an adenoma on CT scanning showed CYP11B2 staining in the adenoma. Furthermore, 5 cases of an unilateral adenoma, showed CYP11B2 staining in the adjacent adrenal cortex and an absence of staining for CYP11B2 in the adenoma. 5 cases showed CYP11B2 expression is heterogeneously immunolocalized throughout the tumor area.Conclusion: Thus, the functional heterogeneity of adrenal tumors in primary aldosteronism has been proven. It is necessary to compare the data of immunohistochemical studies on the expression of CYP11B2 with the indicators of the level of 18-hydroxycortisol, 18-oxocortisol.

scholarly journals Novel Mutations Detection with Next-Generation Sequencing and Its Association with Clinical Outcome in Unilateral Primary Aldosteronism

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1167
Author(s):  
Che-Hsiung Wu ◽  
Kang-Yung Peng ◽  
Daw-Yang Hwang ◽  
Yen-Hung Lin ◽  
Vin-Cent Wu ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Primary Aldosteronism ◽  
Sanger Sequencing ◽  
Somatic Mutations ◽  
Clinical Success ◽  
Clinical Success Rate ◽  
Driver Gene ◽  
Next Generation ◽  
Driver Genes ◽  
Generation Sequencing

Somatic mutations have been identified in adrenal tissues of unilateral primary aldosteronism (uPA). The spectrum of somatic mutations in uPAs was investigated using a customized and targeted next-generation sequencing (cNGS) approach. We also assessed whether cNGS or Sanger sequencing-identified mutations have an association with clinical outcomes in uPA. Adrenal tumoral tissues of uPA patients who underwent adrenalectomy were obtained. Conventional somatic mutation hotspots in 240 extracted DNA samples were initially screened using Sanger sequencing. A total of 75 Sanger-negative samples were further investigated by sequencing the entire coding regions of the known aldosterone-driver genes by our cNGS gene panel. Somatic mutations in aldosterone-driver genes were detected in 21 (28%) of these samples (8.8% of all samples), with 9 samples, including mutations in CACNA1D gene (12%), 5 in CACNA1H (6.6%), 3 in ATP2B3 (4%), 2 in CLCN2 (2.6%), 1 in ATP1A1 (1.3%), and 1 in CTNNB1 (1.3%). Via combined cNGS and Sanger sequencing aldosterone-driver gene mutations were detected in altogether 186 of our 240 (77.5%) uPA samples. The complete clinical success rate of patients containing cNGS-identified mutations was higher than those without mutations (odds ratio (OR) = 10.9; p = 0.012). Identification of somatic mutations with cNGS or Sanger sequencing may facilitate the prediction of complete clinical success after adrenalectomy in uPA patients.

scholarly journals Unravelling the Genetic Basis of Primary Aldosteronism

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 875
Author(s):  
Niki Mourtzi ◽  
Amalia Sertedaki ◽  
Athina Markou ◽  
George P. Piaditis ◽  
Evangelia Charmandari
Keyword(s):  
Primary Aldosteronism ◽  
Genetic Basis ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Germline Mutations ◽  
Secondary Hypertension ◽  
Diagnostic Tools ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Made In

Primary aldosteronism (PA), a condition characterized by autonomous aldosterone hypersecretion, constitutes the most common cause of secondary hypertension. Over the last decade, major breakthroughs have been made in the field of genetics underpinning PA. The advent and wide application of Next Generation Sequencing (NGS) technology led to the identification of several somatic and germline mutations associated with sporadic and familial forms of PA. Somatic mutations in ion-channel genes that participate in aldosterone biosynthesis, including KCNJ5, CACNA1D, ATP1A1, and ATP2B3, have been implicated in the development of aldosterone-producing adenomas (APAs). On the other hand, germline variants in CLCN2, KCNJ5, CACNA1H, and CACNA1D genes have been implicated in the pathogenesis of the familial forms of PA, FH-II, FH-III, and F-IV, as well as PA associated with seizures and neurological abnormalities. However, recent studies have shown that the prevalence of PA is higher than previously thought, indicating the need for an improvement of our diagnostic tools. Further research is required to recognize mild forms of PA and to investigate the underlying molecular mechanisms.

Sign in / Sign up

Export Citation Format

Share Document