Somatic PRKACA Mutations: Association With Transition From Pituitary-Dependent to Adrenal-Dependent Cushing Syndrome
| Autor: | Kerstin Bathon, Guido Di Dalmazi, Ad R. M. M. Hermus, Henri J L M Timmers, Giorgio Arnaldi, Felix Beuschlein, Davide Calebiro, Marina Scarpelli, Martin Reincke, Benno Küsters |
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| Přispěvatelé: | Di Dalmazi G., Timmers H.J.L.M., Arnaldi G., Kusters B., Scarpelli M., Bathon K., Calebiro D., Beuschlein F., Hermus A., Reincke M. |
| Rok vydání: | 2019 |
| Předmět: |
Adult
0301 basic medicine medicine.medical_specialty Endocrinology Diabetes and Metabolism Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] Clinical Biochemistry 030209 endocrinology & metabolism Context (language use) Biochemistry 03 medical and health sciences Cushing syndrome All institutes and research themes of the Radboud University Medical Center 0302 clinical medicine Endocrinology Internal medicine Adrenal Glands medicine Humans Missense mutation Pituitary ACTH Hypersecretion Cushing Syndrome Cushing´s disease PRKACA PKA macronodular hyperplasia transition Cyclic AMP-Dependent Protein Kinase Catalytic Subunits Adrenal cortex business.industry Biochemistry (medical) Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16] Cushing's disease Hyperplasia Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] medicine.disease Cushing Disease PRKACA Cross-Sectional Studies 030104 developmental biology medicine.anatomical_structure Female business |
| Zdroj: | Journal of Clinical Endocrinology and Metabolism, 104, 5651-5657 Journal of Clinical Endocrinology and Metabolism, 104, 11, pp. 5651-5657 |
| ISSN: | 0021-972X |
| Popis: | ContextProlonged adrenal stimulation by corticotropin, as in long-standing Cushing disease (CD), leads to diffuse to nodular hyperplasia. Adrenal functional autonomy has been described in a subset of patients with CD, leading to the hypothesis of transition from ACTH-dependent to ACTH-independent hypercortisolism.ObjectiveWith the consideration that the catalytic α subunit of protein kinase A (PKA; PRKACA) somatic mutations are the most common finding in adrenal adenomas associated with ACTH-independent Cushing syndrome, our aim was to analyze PRKACA mutations in adrenals of patients with persistent/long-standing CD.DesignCross-sectional.SettingUniversity hospital.PatientsTwo patients with long-standing CD and suspicion of coexistence of autonomous adrenal hyperfunction, according to pre and postoperative evaluations, were selected for this study, following an intensive literature search and patient-chart reviewing.InterventionClinical data were analyzed. DNA was extracted from adrenal tissue for PRKACA sequencing. PKA activity was assayed.Main Outcome MeasurePRKACA somatic mutations.ResultsBoth patients showed mutations of PRKACA in the macronodule in the context of micronodular adrenal hyperplasia. One patient harbored the previously described p.Leu206Arg substitution, whereas a p.Ser213Arg missense variation was detected in the adrenal nodule of the second patient. No mutations were detected in the adjacent adrenal cortex of the second patient. In silico analysis predicts that p.Ser213Arg can interfere with the interaction between the regulatory and catalytic subunits of PKA.ConclusionsOur study shows that PRKACA somatic mutations can be found in adrenal nodules of patients with CD. These genetic alterations could represent a possible mechanism underlying adrenal nodule formation and autonomous cortisol hyperproduction in a subgroup of patients with long-standing CD. |
| Databáze: | OpenAIRE |
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