title: Phosphodiesterase 11A (PDE11A) gene defects in patients with acth-independent macronodular adrenal hyperplasia (AIMAH): functional variants may contribute to genetic susceptibility of bilateral adrenal tumors.
abstract: BACKGROUND
  Phosphodiesterases (PDEs) are key regulatory enzymes of intracellular cAMP levels. PDE11A function has been linked to predisposition to adrenocortical tumors.
  
  
  OBJECTIVE
  The aim of the study was to study the PDE11A gene in a large cohort of patients with ACTH-independent macronodular adrenal hyperplasia (AIMAH) and in control subjects.
  
  
  METHODS
  The PDE11A entire coding region was sequenced in 46 patients with AIMAH and 192 controls. Two variants found in AIMAH patients were transiently expressed in HEK 293 and adrenocortical H295R cells for further functional studies.
  
  
  RESULTS
  The frequency of all PDE11A variants was significantly higher among patients with AIMAH (28%) compared to controls (7.2%) (P = 5 × 10(-5)). Transfection of the two PDE11A variants found in AIMAH patients only (D609N or M878V) showed that cAMP levels were higher, after forskolin stimulation, in cells transfected with the PDE11A mutants, compared to cells transfected with the wild-type PDE11A in HEK 293 cells (P < 0.05). Moreover, transfection with mutants PDE11A increased transcriptional activity of a cAMP-response element reporter construct compared to wild-type PDE11A in HEK 293 cells (P < 0.0004 for D609N and P < 0.003 for M878V) and in the adrenocortical H295R cells (P < 0.05 for D609N and M878V). In addition, analysis of cAMP levels in intact living culture cells by fluorescence resonance energy transfer probes showed increased cAMP in forskolin-treated cells transfected with PDE11A variants compared with wild-type PDE11A (P < 0.05).
  
  
  CONCLUSIONS
  We conclude that PDE11A genetic variants may increase predisposition to AIMAH.
authors.affiliation: Service d'Endocrinologie, Hôpital Cochin 27, rue du Faubourg Saint-Jacques, 75014 Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Vezzosi
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.forename: Camille
authors.initials: C
authors.lastname: Baudry
authors.forename: Marthe
authors.initials: M
authors.lastname: Rizk-Rabin
authors.forename: Anelia
authors.initials: A
authors.lastname: Horvath
authors.forename: Isaac
authors.initials: I
authors.lastname: Levy
authors.forename: Fernande
authors.initials: F
authors.lastname: René-Corail
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.forename: Grégoire
authors.initials: G
authors.lastname: Vandecasteele
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D003480:Cushing Syndrome / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*
chemical_list: D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human