Novel somatic mutations in the catalytic subunit of the protein kinase a as a cause of adrenal Cushing's syndrome: a European multicentric study

Guido Di Dalmazi, Caroline Kisker, Davide Calebiro, Massimo Mannelli, Letizia Canu, Giorgio Arnaldi, Marcus Quinkler, Nada Rayes, Antoine Tabarin, Marie Laure Jullié, Franco Mantero, Beatrice Rubin, Jens Waldmann, Detlef K. Bartsch, Renato Pasquali, Martin Lohse, Bruno Allolio, Martin Fassnacht, Felix Beuschlein, Martin Reincke*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)


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 centerswere 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.

Original languageEnglish
Pages (from-to)E2093-E2100
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Issue number10
Early online date24 Jun 2014
Publication statusPublished - 1 Oct 2014

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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