Novel Somatic Mutations in the Catalytic Subunit of the Protein Kinase A as a Cause of Adrenal Cushing's Syndrome: A European Multicentric Study

Context: Somatic mutations in PRKACA gene, encoding the catalytic subunit of protein kinase A (PKA), have been recently found in a high proportion of sporadic adenomas associated with Cushing's syndrome. The aim was to analyze the PRKACA mutation in a large cohort of patients with adrenocortica...

Full description

Saved in:
Bibliographic Details
Published in:The journal of clinical endocrinology and metabolism 2014-10, Vol.99 (10), p.E2093-E2100
Main Authors: Di Dalmazi, Guido, Kisker, Caroline, Calebiro, Davide, Mannelli, Massimo, Canu, Letizia, Arnaldi, Giorgio, Quinkler, Marcus, Rayes, Nada, Tabarin, Antoine, Laure Jullié, Marie, Mantero, Franco, Rubin, Beatrice, Waldmann, Jens, Bartsch, Detlef K, Pasquali, Renato, Lohse, Martin, Allolio, Bruno, Fassnacht, Martin, Beuschlein, Felix, Reincke, Martin
Format: Article
Language:English
Subjects:
Adrenal Cortex Neoplasms - ethnology
Adrenal Cortex Neoplasms - genetics
Adrenocortical Adenoma - ethnology
Adrenocortical Adenoma - genetics
Adult
Aged
Cushing Syndrome - ethnology
Cushing Syndrome - genetics
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits - genetics
European Continental Ancestry Group - genetics
Female
Heterozygote
Humans
Male
Middle Aged
Mutation
Prevalence
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Context: Somatic mutations in PRKACA gene, encoding the catalytic subunit of protein kinase A (PKA), have been recently found in a high proportion of sporadic adenomas associated with Cushing's syndrome. The aim was to analyze the PRKACA mutation in a large cohort of patients with adrenocortical masses. Methods: Samples from nine European centers were included (Germany, n = 4; Italy, n = 4; France, n = 1). Samples were drawn from 149 patients with nonsecreting adenomas (n = 32 + 2 peritumoral), subclinical hypercortisolism (n = 36), Cushing's syndrome (n = 64 + 2 peritumoral), androgen-producing tumors (n = 4), adrenocortical carcinomas (n = 5 + 2 peritumoral), and primary bilateral macronodular adrenal hyperplasias (n = 8). Blood samples were available from patients with nonsecreting adenomas (n = 15), subclinical hypercortisolism (n = 10), and Cushing's syndrome (n = 35). Clinical and hormonal data were collected. DNA amplification by PCR of exons 6 and 7 of the PRKACA gene and direct sequencing were performed. Results: PRKACA heterozygous mutations were found in 22/64 samples of Cushing's syndrome patients (34%). No mutations were found in peritumoral tissue and blood samples or in other tumors examined. The c.617A>C (p.Leu206Arg) occurred in 18/22 patients. Furthermore, two novel mutations were identified: c.600_601insGTG/p.Cys200_Gly201insVal in three patients and c.639C>G+c.638_640insATTATCCTGAGG/p.Ser213Arg+p.Leu212_Lys214insIle-Ile-Leu-Arg) in one. All the mutations involved a region implicated in interaction between PKA regulatory and catalytic subunits. Patients with somatic PRKACA mutations showed higher levels of cortisol after dexamethasone test and a smaller adenoma size, compared with nonmutated subjects. Conclusions: These data confirm and extend previous observations that somatic PRKACA mutations are specific for adrenocortical adenomas causing Cushing's syndrome.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2014-2152