title: Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome.
abstract: BACKGROUND
  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.
  
  
  METHODS
  We performed exome sequencing of tumor-tissue specimens from 10 patients with cortisol-producing adrenal adenomas and evaluated recurrent mutations in candidate genes in an additional 171 patients with adrenocortical tumors. We also performed genomewide copy-number analysis in 35 patients with cortisol-secreting bilateral adrenal hyperplasias. We studied the effects of these genetic defects both clinically and in vitro.
  
  
  RESULTS
  Exome sequencing revealed somatic mutations in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase (protein kinase A [PKA]), in 8 of 10 adenomas (c.617A→C in 7 and c.595_596insCAC in 1). Overall, PRKACA somatic mutations were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing's syndrome; these mutations were not detectable in 40 patients with subclinical hypercortisolism or in 82 patients with other adrenal tumors. Among 35 patients with cortisol-producing hyperplasias, 5 (including 2 first-degree relatives) carried a germline copy-number gain (duplication) of the genomic region on chromosome 19 that includes PRKACA. In vitro studies showed impaired inhibition of both PKA catalytic subunit mutants by the PKA regulatory subunit, whereas 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
  Genetic alterations of the catalytic subunit of PKA were found to be associated with human disease. Germline duplications of this gene resulted in bilateral adrenal hyperplasias, whereas somatic PRKACA mutations resulted in unilateral cortisol-producing adrenal adenomas. (Funded by the European Commission Seventh Framework Program and others.).
authors.affiliation: The authors' affiliations are listed in the Appendix.
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.forename: Guillaume
authors.initials: G
authors.lastname: Assié
authors.forename: Davide
authors.initials: D
authors.lastname: Calebiro
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.forename: Andrea
authors.initials: A
authors.lastname: Osswald
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Ronchi
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.forename: Silviu
authors.initials: S
authors.lastname: Sbiera
authors.forename: Fabio R
authors.initials: FR
authors.lastname: Faucz
authors.forename: Katrin
authors.initials: K
authors.lastname: Schaak
authors.forename: Anett
authors.initials: A
authors.lastname: Schmittfull
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarzmayr
authors.forename: Olivia
authors.initials: O
authors.lastname: Barreau
authors.forename: Delphine
authors.initials: D
authors.lastname: Vezzosi
authors.forename: Marthe
authors.initials: M
authors.lastname: Rizk-Rabin
authors.forename: Ulrike
authors.initials: U
authors.lastname: Zabel
authors.forename: Eva
authors.initials: E
authors.lastname: Szarek
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Salpea
authors.forename: Antonella
authors.initials: A
authors.lastname: Forlino
authors.forename: Annalisa
authors.initials: A
authors.lastname: Vetro
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
authors.forename: Caroline
authors.initials: C
authors.lastname: Kisker
authors.forename: Susanne
authors.initials: S
authors.lastname: Diener
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lohse
authors.forename: Martin
authors.initials: M
authors.lastname: Reincke
authors.forename: Jérome
authors.initials: J
authors.lastname: Bertherat
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Bruno
authors.initials: B
authors.lastname: Allolio
mesh_terms: D000236:Adenoma / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D000310:Adrenal Gland Neoplasms / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D000328:Adult; D020134:Catalytic Domain; D003480:Cushing Syndrome / Q000201:enzymology / Q000209:etiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D018095:Germ-Line Mutation; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis; D008875:Middle Aged; D009154:Mutation; D011487:Protein Conformation; D017422:Sequence Analysis, DNA
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D006854:Hydrocortisone