title: Novel somatic mutations in the catalytic subunit of the protein kinase A as a cause of adrenal Cushing's syndrome: a European multicentric study.
abstract: BACKGROUND
  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.
authors: Medizinische Klinik und Poliklinik IV (G.D.D., M.F., F.B., M.R.), Klinikum der Universität München, München, Germany; Rudolf Virchow Center for Experimental Biomedicine (C.K., D.C., M.L.), University of Würzburg, Würzburg, Germany; Institute of Pharmacology and Toxicology (D.C., M.L.), University of Würzburg, 97080 Würzburg, Germany; Department of Experimental and Clinical Biomedical Sciences (M.M., L.C.), Florence, Italy; Endocrinology Division, Department of Clinical and Molecular Sciences (G.A.), University Hospital, Ancona, Italy; Bereich Klinische Endokrinologie, Charité Campus Mitte (M.Q.), Charité Universitätsmedizin, Berlin, Germany; Department of General, Visceral, and Transplant Surgery (N.R.), Charité Campus Virchow Clinic, Berlin, Germany; Department of Endocrinology (A.T.), Centre Hospitalier Universitaire Bordeaux and University of Bordeaux, Bordeaux, France; Service d'Anatomopathologie (L.J.), Centre Hospitalier Universitaire Bordeaux and University of Bordeaux, Bordeaux, France; Endocrinology Unit, Department of Medicine (F.M., B.R.), University of Padua, Padua, Italy; Klinik für Visceral, Thorax, und Gefäßchirurgie (J.W., D.K.B.), Marburg, Germany; Endocrinology Unit, Department of Medical and Surgical Sciences (R.P.), Alma Mater University of Bologna, Bologna, Italy; Endocrine and Diabetes Unit, Department of Internal Medicine I (B.A.), University Hospital, University of Würzburg, Würzburg, Germany; and Comprehensive Cancer Center Mainfranken (M.F.), University of Würzburg, Germany.
authors: Guido
authors: G
authors: Di Dalmazi
authors: Caroline
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authors: Kisker
authors: Davide
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authors: Calebiro
authors: Massimo
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authors: Mannelli
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authors: Canu
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authors: Rayes
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authors: Lohse
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authors: Allolio
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authors: Fassnacht
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authors: Beuschlein
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authors: Reincke
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000208:ethnology / Q000235:genetics*; D018246:Adrenocortical Adenoma / Q000208:ethnology / Q000235:genetics*; D000328:Adult; D000368:Aged; D003480:Cushing Syndrome / Q000208:ethnology / Q000235:genetics*; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D044465:White People / Q000235:genetics
chemical_list: D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human