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

Research output: Contribution to journalArticle


  • Guido Di Dalmazi
  • Caroline Kisker
  • 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

Colleges, School and Institutes

External organisations

  • Ludwig-Maximilians-Universität LMU
  • Rudolf Virchow Center
  • University of Wurzburg
  • Department of Experimental and Clinical Biomedical Sciences
  • University Hospital
  • Charité-Universitätsmedizin Berlin
  • University of Bordeaux
  • University of Padova Dep. Pure and Applied Mathematics Via Trieste
  • Klinik für Visceral, Thorax, und Gefäßchirurgie
  • Università di Bologna
  • Department of Experimental and Clinical Biomedical Sciences


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