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 IN VIVO AND IN VITRO STUDIES OF ADRENAL SECRETIONS IN CUSHING'S SYNDROME AND PRIMARY ALDOSTERONISM*

1963 ◽  
Vol 42 (4) ◽  
pp. 516-524 ◽  
Author(s):  
Edward G. Biglieri ◽  
Satoshi Hane ◽  
Paul E. Slaton ◽  
Peter H. Forsham
Keyword(s):  
Cushing’S Syndrome ◽  
Primary Aldosteronism ◽  
Cushing's Syndrome ◽  
In Vitro Studies

scholarly journals Long term control of hypercortisolism with fluconazole: case report and in vitro studies

2006 ◽  
Vol 154 (4) ◽  
pp. 519-524 ◽  
Author(s):  
Michaela Riedl ◽  
Christina Maier ◽  
Georg Zettinig ◽  
Peter Nowotny ◽  
Wolfgang Schima ◽  
...  
Keyword(s):  
Case Report ◽  
Cell Line ◽  
Cushing’S Syndrome ◽  
Adrenal Adenoma ◽  
Cushing's Syndrome ◽  
Unilateral Adrenalectomy ◽  
Cortisol Excretion ◽  
Glucocorticoid Production

Objectives: To evaluate the efficacy of fluconazole as an alternative treatment for controlling hypercortisolism in Cushing’s syndrome and to determine its effect on glucocorticoid production in vitro. Design: Case report and in vitro study in a University Clinic. Case: An 83 year old patient presented with recurrence of Cushing’s syndrome due to pulmonary metastases three years after unilateral adrenalectomy. During a near fatal episode of sepsis she was started on fluconazole 200 mg/day intravenously which normalised cortisol excretion. The therapy was continued orally for 18 months. Upon temporary discontinuation and reintroduction of treatment, cortisol levels increased and normalized, respectively. At month 16, fluconazole had to be increased to a dose of 400 mg/day to keep cortisol excretion in the normal range. Disease progression was slow and no side effects occurred. In vitro results: Fluconazole in a concentration of 500 μM nearly abolished corticosterone production over 24 h from the adrenal adenoma cell line Y-1 (8.6 ± 0.5% compared with control, P < 0.0001) and significantly reduced corticosterone production in concentrations of 50 μM (48.3 ± 1.9% vs. control, P < 0.0001) and 5 μM (80.5 ± 8.5% vs. control, P < 0.05). Conclusion: These results demonstrate for the first time that fluconazole normalises cortisol concentrations in vivo in a patient with Cushing’s syndrome with adrenal carcinoma and inhibit glucocorticoid production in vitro in a cell line. Thus, fluconazole might be useful in controlling glucocorticoid excess in Cushing’s syndrome and because of its lower toxicity might be preferable to ketoconazole.

scholarly journals Orbital manifestations of hypercorticism

2021 ◽  
Vol 16 (4) ◽  
pp. 4-13
Author(s):  
Maria O. Korchagina ◽  
Alexey A. Trukhin ◽  
Natalya Yu. Sviridenko
Keyword(s):  
Cushing’S Syndrome ◽  
Molecular Mechanisms ◽  
Cushing's Syndrome ◽  
The Body ◽  
Graves Disease ◽  
Fatty Tissue ◽  
Factors Affecting ◽  
Ocular Manifestations

Nowadays, Cushing's syndrome (hypercortisolism) and its manifestations are well studied. The main symptoms of hyper-cortisolism are obesity, osteoporosis, cardiomyopathy, muscle atrophy, skin thinning and purple stretch marks (striae) on the body. In practice, obesity and osteoporosis are the most frequent symptoms that are found in 90% of cases. However, there are some patients with an implicit clinical picture of hypercorticism. Some cases might concomitant with exophthalmos. This review describes a rare symptom of hypercortisolism — exophthalmos. Exophthalmos is a pathological protruding of eyeballs. This symptom is known in the context of TED that occurs most commonly in patients with Graves' disease. The article compares the mechanisms of development of eye symptoms in Cushing's syndrome and thyroid diseases, especially the Graves' disease. It discusses possible molecular mechanisms leading to exophthalmia in patients with Cushing's syndrome. Factors affecting adipogenesis in vitro and in vivo are studied, in particular factors leading to an increase of orbital fatty tissue against of elevated cortisol levels. Hormonal signaling and transcription cascades responsible for adipocyte differentiation into mature fat cells are presented. Other orbital manifestations of hypercortisolism, which occur relatively rare in practice, are also discussed in the article. These include glaucoma as well as cataract, Lisha nodules and central serous chorioretinopathy. Clinical cases of Cushing's syndrome with different ocular manifestations are considered and appropriate conclusions have been drawn.

scholarly journals Biochemical and Functional Characterization of Anthocyanidin Reductase (ANR) from Mangifera indica L.

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2876 ◽  
Author(s):  
Lin Tan ◽  
Mei Wang ◽  
Youfa Kang ◽  
Farrukh Azeem ◽  
Zhaoxi Zhou ◽  
...  
Keyword(s):  
Enzyme Assay ◽  
Molecular Mechanisms ◽  
Mangifera Indica ◽  
Functional Characterization ◽  
Citrate Buffer ◽  
Anthocyanidin Reductase ◽  
High Amino Acid ◽  
Optimum Ph

Mango (Mangifera indica L.) is abundant in proanthocyanidins (PAs) that are important for human health and plant response to abiotic stresses. However, the molecular mechanisms involved in PA biosynthesis still need to be elucidated. Anthocyanidin reductase (ANR) catalyzes a key step in PA biosynthesis. In this study, three ANR cDNAs (MiANR1-1,1-2,1-3) were isolated from mango, and expressed in Escherichia coli. In vitro enzyme assay showed MiANR proteins convert cyanidin to their corresponding flavan-3-ols, such as (−)-catechin and (−)-epicatechin. Despite high amino acid similarity, the recombinant ANR proteins exhibited differences in enzyme kinetics and cosubstrate preference. MiANR1-2 and MiANR1-3 have the same optimum pH of 4.0 in citrate buffer, while the optimum pH for MiANR1-1 is pH 3.0 in phosphate buffer. MiANR1-1 does not use either NADPH or NADH as co-substrate while MiANR1-2/1-3 use only NADPH as co-substrate. MiANR1-2 has the highest Km and Vmax for cyanidin, followed by MiANR1-3 and MiANR1-1. The overexpression of MiANRs in ban mutant reconstructed the biosynthetic pathway of PAs in the seed coat. These data demonstrate MiANRs can form the ANR pathway, leading to the formation of two types of isomeric flavan-3-ols and PAs in mango.

scholarly journals Cellular and molecular abnormalities of a macronodular adrenal hyperplasia causing beta-blocker-sensitive Cushing's syndrome

2007 ◽  
Vol 51 (9) ◽  
pp. 1452-1462 ◽  
Author(s):  
Tânia L. Mazzuco ◽  
Michaël Thomas ◽  
Monique Martinie ◽  
Nadia Cherradi ◽  
Nathalie Sturm ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Cultured Cells ◽  
Cushing's Syndrome ◽  
Screening Tests ◽  
Adrenal Hyperplasia ◽  
Hormone Production ◽  
Autocrine Loop ◽  
Molecular Alterations ◽  
Molecular Abnormalities

Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia (AIMAH) can be associated with abnormal responses of aberrantly expressed adrenocortical receptors. This study aimed to characterize in vitro the pathophysiology of hypercortisolism in a b-blocker-sensitive Cushing's syndrome due to AIMAH. Cortisol secretion profile under aberrant receptors stimulation revealed hyperresponsiveness to salbutamol (beta2-adrenoceptor agonist), cisapride (5-HT4 receptor agonist), and vasopressin in AIMAH cultured cells, but not in normal adrenocortical cells. By RT-PCR, AIMAH tissues revealed beta2-adrenoceptor overexpression rather than ectopical expression. MC2R expression was similar in both AIMAH and normal adrenocortical tissues. Curiously, cortisol levels of AIMAH cells under basal condition were 15-fold higher than those of control cells and were not responsive to ACTH. Analysis of culture medium from AIMAH cells could detect the presence of ACTH, which was immunohistochemically confirmed. Finally, the present study of AIMAH cells has identified: a) cortisol hyperresponsiveness to catecholamines, 5-HT4 and vasopressin in vitro, in agreement with clinical screening tests; b) abnormal expression of beta2-adrenoceptors in some areas of the hyperplastic adrenal tissue; c) autocrine loop of ACTH production. Altogether, the demonstration of aberrant responses to hormonal receptors and autocrine hormone production in the same tissue supports the assumption of multiple molecular alterations in adrenal macronodular hyperplasia.

STUDIES ON THE IN VITRO PRODUCTION OF CORTICOSTEROIDS BY ADRENAL GLANDS FROM NORMOTENSIVE INDIVIDUALS AND HYPERTENSIVE PATIENTS

1962 ◽  
Vol 40 (1) ◽  
pp. 285-301 ◽  
Author(s):  
Jean Davignon ◽  
Erich Koiw ◽  
Wojciech Nowaczynski ◽  
Gilles Tremblay ◽  
Jacques Genest
Keyword(s):  
Cushing’S Syndrome ◽  
Adrenal Glands ◽  
Cushing's Syndrome ◽  
The Other ◽  
Malignant Hypertension ◽  
Unit Weight ◽  
Chromatographic Technique ◽  
Acth Stimulation ◽  
The Mean

The production of aldosterone and other corticosteroids by adrenal glands surgically removed from 5 normotensive subjects with renal disease of various types, 11 patients with arterial hypertension, and 2 with Cushing's syndrome was investigated in vitro by the incubation chromatographic technique. The rate of steroid formation per unit weight of tissue was markedly lower in severe and malignant hypertension and slightly higher in benign hypertension as compared with the rate in normotensive controls. The amount of steroid released varied widely from one gland to the other and showed marked overlapping between the various groups; these variations were most prominent in benign hypertension, less in the normotensive group, and least evident in severe and malignant hypertension. The response of steroidogenesis to ACTH stimulation in vitro was slightly reduced in severe and malignant hypertension. The mean output of aldosterone by adrenal glands from hypertensives was slightly above the mean value obtained with normotensive control glands. The percentage of aldosterone formation in respect to total steroid production was roughly correlated with the severity of hypertension. In four hyperplastic adrenals obtained from two cases of Cushing's syndrome, the in vitro formation of steroids per unit weight of tissue and the response to ACTH did not differ significantly from that found in glands obtained from the other patients under study. The value of in vitro studies for the assessment of the functional capacity of the adrenal cortex is discussed.

scholarly journals KCNJ5 Somatic Mutation Is a Predictor of Hypertension Remission After Adrenalectomy for Unilateral Primary Aldosteronism

2019 ◽  
Vol 104 (10) ◽  
pp. 4695-4702 ◽  
Author(s):  
Leticia A P Vilela ◽  
Marcela Rassi-Cruz ◽  
Augusto G Guimaraes ◽  
Caio C S Moises ◽  
Thais C Freitas ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Somatic Mutation ◽  
Primary Aldosteronism ◽  
Antihypertensive Drugs ◽  
Independent Predictor ◽  
Blood Pressure Response ◽  
Antihypertensive Medications ◽  
Unilateral Adrenalectomy ◽  
Molecular Features ◽  
Endocrine Hypertension

AbstractContextPrimary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure <140/90 mm Hg without antihypertensive drugs) has been reported in approximately 50% of patients with unilateral PA after adrenalectomy. HT duration and severity are predictors of blood pressure response, but the prognostic role of somatic KCNJ5 mutations is unclear.ObjectiveTo determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA.MethodsWe retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases.ResultsKCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu168Arg (n = 15), and p.Glu145Gln (n = 1). HT remission was reported in 37 of 100 (37%) patients. Among patients with HT remission, 73% were women (P = 0.04), 48.6% used more than three antihypertensive medications (P = 0.0001), and 64.9% had HT duration <10 years (P = 0.0015) compared with those without HT remission. Somatic KCNJ5 mutations were associated with female sex (P = 0.004), larger nodules (P = 0.001), and HT remission (P = 0.0001). In multivariate analysis, only a somatic KCNJ5 mutation was an independent predictor of HT remission after adrenalectomy (P = 0.004).ConclusionThe presence of a KCNJ5 somatic mutation is an independent predictor of HT remission after unilateral adrenalectomy in patients with unilateral PA.

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