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Constitutive activation of PRKACA in adrenal Cushing's syndrome

Monday, September 22, 2014 — Poster Session II

4:00 p.m. – 6:00 p.m.

FAES Academic Center



* FARE Award Winner


  • C Stratakis
  • F Beuschleni
  • M Fassnacht
  • G Assié
  • D Calebiro
  • FR Faucz
  • A Osswald
  • CL Ronchi
  • T Wieland
  • S Sbiera
  • K Schaak
  • A Schmittfull
  • T Schwarzmayr
  • O Barreau
  • D Vezzosi
  • M Rizk-Rabbin
  • U Zabel
  • E Szarek
  • P Salpea
  • A Forlino


Corticotropin-independent Cushing’s syndrome may be caused by tumors or hyperplasia of the adrenal cortex. The aim of this study was the analysis of the genetic basis of CS in order to reveal the gene/s responsible for the disease. Exome sequencing was performed in cortisol-producing adenomas (CPAs) and hyperplasias (BAH) and recurrent mutations in candidate genes. Genome-wide copy number analysis was also performed. The effects of these genetic defects were studied both clinically and in vitro. Exome sequencing revealed somatic mutations in the PRKACA gene, which encodes the main catalytic subunit of cyclic AMP-dependent protein kinase (PKA in a total of 22/59 (37%) adenomas from patients with overt CS. Among 35 patients with BAH, five carried germline copy number gain of the chromosome 19 region including the PRKACA gene. In vitro studies showed increased PKA activity in all cases with defects. Thus, more than one third of CPAs associated with overt CS harbor unique somatic mutations of the main cAMP-dependent kinase catalytic subunit, PRKACA resulting in constitutive PKA activation. Germline duplication of the PRKACA gene was identified in BAH. This is the first report of genetic alterations of the catalytic subunit of PKA linked to human disease.

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