ECE2014 Oral Communications Adrenal clinical (5 abstracts)
Constitutive activation of PRKACA in adrenal Cushing’s syndrome
Felix Beuschlein 1 , Martin Fassnacht 1, , Guilaume Assié 4, , Davide Calebiro 6, , Constantine A. Stratakis 8 , Andrea Osswald 1 , Cristina L. Ronchi 9 , Thomas Wieland 10 , Silviu Sbiera 1, , Fabio R. Faucz 8 , Katrin Schaak 1 , Anett Schmittfull 9 , Caroline Kisker 7 , Susanne Diener 10 , Thomas Meitinger 10, , Martin J. Lohse 6, , Martin Reincke 1 , Jérome Bertherat 4, , Tim M. Strom 10, & Bruno Allolio 2,
1Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, München, Germany; 2Department of Medicine I, Endocrine and Diabetes Unit, University Hospital, University of Würzburg, Würzburg, Germany; 3Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany; 4INSERM U1016, CNRS UMR 8104, Institut Cochin, Faculté de Médecine Paris Descartes, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; 5Department of Endocrinology, Referral Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France; 6Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany; 7Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany; 8Section on Endocrinology & Genetics (SEGEN), Program on Developmental Endocrinology & Genetics (PDEGEN), NICHD, NIH, Bethesda, Maryland, USA; 9Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany; 10Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; 11Institute of Human Genetics, Technische Universität München, München, Germany; 12DZHK (German Centre for Cardiovascular Research) partner site, Munich Heart Alliance, München, Germany.
Background and Methods: Corticotropin-independent Cushing’s syndrome is caused by tumors or hyperplasia of the adrenal cortex. The molecular pathogenesis of cortisol producing adrenal adenomas is not well understood. Therefore, exome sequencing was performed in 10 cortisol-producing adenomas and recurrent mutations in candidate genes were evaluated in additional 171 patients with adrenocortical tumors. In addition, genome-wide copy number analysis was performed in 35 patients with cortisol-secreting bilateral hyperplasias. The effects of these genetic defects were studied both clinically and in vitro.
Results: Exome sequencing revealed somatic mutations in the PRKACA gene, which encodes the main catalytic subunit of cyclic AMP-dependent protein kinase (PKA), in eight of ten adenomas (c.617A>C in seven and c.595_596insCAC in one). Overall, PRKACA somatic mutations were identified in a total of 22 of 59 adenomas (37%) from patients with overt Cushing’s syndrome while these mutations were not detectable in patients with subclinical hypercortisolism (n=40) or in other adrenal tumors (n=82). Among 35 patients with cortisol- producing hyperplasias, 5 (two of whom were first-degree relatives) carried a germline copy number gain of the chromosome 19 region including the PRKACA gene. In vitro studies demonstrated impaired inhibition of both PKA catalytic subunit mutants by the PKA regulatory subunit, while cells from patients with germline chromosomal gains showed increased protein levels of the PKA catalytic subunit; in both instances, basal PKA activity was increased.
Conclusions: Taken together this report links genetic alterations of the main catalytic subunit of PKA to human disease: germline duplications of this gene cause bilateral adrenal hyperplasias, whereas somatic PRKACA mutations lead to unilateral cortisol-producing adrenal adenomas. This is consistent with the known role of the cAMP signaling pathway in adrenal lesions associated with Cushing’s syndrome.
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more